β3 adrenergic agonists

ABSTRACT

The present invention relates to a β3 adrenergic receptor agonist of formula (I); or a pharmaceutical salt thereof; which is capable of increasing lipolysis and energy expenditure in cells and, therefore, is useful, e.g., for treating Type 2 diabetes and/or obesity

This application is a National filing under 35 U.S.C. § 371 ofPCT/US02/21317, filed Aug. 6, 2002, which claims the benefit under 35U.S.C. §119(e) of U.S. patent application No. 60/312,275 filed Aug. 14,2001.

The present invention is in the field of medicine, particularly in thetreatment of Type 2 diabetes and obesity. More specifically, the presentinvention relates to β₃ adrenergic receptor agonists useful in thetreatment of Type 2 diabetes and obesity.

The current preferred treatment for Type 2, non-insulin dependentdiabetes as well as obesity is diet and exercise, with a view towardweight reduction and improved insulin sensitivity. Patient compliance,however, is usually poor. The problem is compounded by the fact thatthere are currently no approved medications that adequately treat eitherType 2 diabetes or obesity.

One therapeutic opportunity that has recently been recognized involvesthe relationship between adrenergic receptor stimulation andanti-hyperglycemic effects. Compounds that act as β₃ receptor agonistshave been shown to exhibit a marked effect on lipolysis, thermogenesisand serum glucose levels in animal models of Type 2 (non-insulindependent) diabetes.

The β₃ receptor, which is found in several types of human tissueincluding human fat tissue, has roughly 50% homology to the β₁ and β₂receptor subtypes yet is considerably less abundant. Stimulation of theβ₁ and β₂ receptors can cause adverse effects such as tachycardia,arrhythmia, or tremors. An agonist that is selective for the β₃ receptorover the β₁ and β₂ receptors is, therefore, more desirable for treatingType 2 diabetes or obesity relative to a non-selective agonist.

However, recent studies have suggested the presence of an atypical βreceptor associated with atrial tachycardia in rats (Br. J. ofPharmacol., 18:2085–2098, 1996). In other words, compounds that are notagonists of the β₁ and β₂ receptors can still modulate tachycardiathrough activation of a yet to be discovered β₄ or through some otherunknown pathway.

A large number of publications have appeared in recent years reportingsuccess in discovery of agents that stimulate the β₃ receptor. Despitethese recent developments, there remains a need to develop a selectiveβ₃ receptor agonist which has minimal agonist activity against the β₁and β₂ receptors.

The present invention relates to a compound of formula I:

wherein:

the dashed line represents a single or double bond;

m is 0, 1 or 2;

A¹, A² and A³ are carbon or nitrogen provided that only one of A¹, A²and A³ can be nitrogen;

D is NR⁸, O or S;

Het is an optionally substituted, optionally benzofused 5 or 6 memberedheterocyclic ring;

R¹ and R² are independently H, halo, hydroxy, C₁–C₆ alkyl, C₁–C₆ alkoxy,C₁–C₄ haloalkyl, or SO₂(C₁–C₆ alkyl);

R³ is H or C₁–C₆ alkyl;

R⁴ forms a bond with X² or is H, cyano, C₁–C₆ alkyl, CONR⁹R⁹ or CO₂R⁹;

R⁵ forms a bond with X² or is H or C₁–C₆ alkyl;

R⁶ is independently at each occurrence halo, hydroxy, cyano, C₁–C₆alkyl, C₁–C₄ haloalkyl or C₁–C₆ alkoxy;

R⁷ is H, CO₂R¹⁰, CONR¹⁰R¹⁰, CH═CHR¹¹, CH₂CH₂R¹¹, NR¹⁰R¹⁰, NR¹⁰SO₂R¹⁰,O(CR¹²R¹³)_(n)R¹⁴, O(CR¹²R¹³)_(p)R¹⁵, SO₂R¹⁰, SO₂NR¹⁰R¹⁰, optionallysubstituted phenyl or optionally substituted heterocycle;

R⁸ forms a bond with X² or is H or C₁–C₆ alkyl;

R⁹ and R¹⁰ are independently at each occurrence H, C₁–C₆ alkyl orphenyl; or when two R⁹ or two R¹⁰ moieties are connected to the samenitrogen atom, then said R⁹ or R¹⁰ moieties may combine with thenitrogen to which they are attached to form a pyrollidinyl, piperidinylor hexamethyleneimino ring;

R¹¹ is cyano, CO₂R¹⁶, CONR¹⁶R¹⁶, CONR¹⁶SO₂R¹⁶, SO₂R¹⁶, heterocycle oroptionally substituted phenyl;

R¹² and R¹³ are independently at each occurrence H or C₁–C₆ alkyl;

R¹⁴ is hydrogen, CO₂R¹⁷, CONR¹⁷R¹⁷, SO₂R¹⁷, SO₂NR¹⁷R¹⁷, optionallysubstituted phenyl or optionally substituted heterocycle,

R¹⁵ is cyano, NR¹⁸R¹⁸, NR¹⁸SO₂R¹⁸ or OR¹⁸;

R¹⁶, R¹⁷ and R¹⁸ are independently at each occurrence H, C₁–C₆ alkyl orphenyl; or when two R¹⁶ or two R¹⁷ or two R¹⁸ moieties are connected tothe same nitrogen atom, then said R¹⁶ or R¹⁷ or R¹⁸ moieties may combinewith the nitrogen to which they are attached to form a pyrollidinyl,piperidinyl or hexamethyleneimino ring;

n is 0, 1, 2 or 3;

p is 1, 2 or 3;

X is absent or is OCH₂ or SCH₂;

X¹ is absent or is (CR¹⁹R²⁰)_(q);

X² is absent or is CO, CONR²¹ or NR²¹CO;

q is 1, 2, 3, 4 or 5;

R¹⁹ and R²⁰ are independently at each occurrence H or C₁–C₆ alkyl; orR¹⁹ and R²⁰ combine with the carbon to which they are both attached toform a C₃–C₇ carbocyclic ring; and

R²¹ is H or C₁–C₆ alkyl; or a pharmaceutical salt thereof.

The present invention also relates to processes for preparing, as wellas novel pharmaceutical formulations containing, a compound of formulaI. In another embodiment, the pharmaceutical formulations of the presentinvention may be adapted for use in treating Type 2 diabetes and obesityand for agonizing the β₃ receptor.

The present invention also relates to methods for treating Type 2diabetes and obesity, as well as a method for agonizing the β₃ receptoremploying a compound of formula I.

In addition, the present invention relates to a compound of formula Ifor use in treating Type 2 diabetes and obesity as well as a compound offormula I for use in agonizing the β₃ receptor. The present invention isfurther related to the use of a compound of formula I for themanufacture of a medicament for treating Type 2 diabetes and obesity asa well as for agonizing the β₃ receptor.

For the purposes of the present invention, as disclosed and claimedherein, the following terms are defined below.

The term “halo” represents fluoro, chloro, bromo, or iodo.

The term “C₁–C₆ alkyl” represents a straight, branched or cyclichydrocarbon moiety having from one to six carbon atoms, e.g., methyl,ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, sec-butyl,t-butyl, cyclobutyl, pentyl, cyclopentyl, hexyl, cyclohexyl and thelike. The term “C₁–C₄ alkyl” refers specifically to methyl, ethyl,n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, sec-butyl, t-butyland cyclobutyl. A “C₁–C₄ haloalkyl” group is a C₁–C₄ alkyl moietysubstituted with up to six halo atoms, preferably one to three haloatoms. An example of a haloalkyl group is trifluoromethyl. A “C₁–C₆alkoxy” group is a C₁–C₆ alkyl moiety connected through an oxy linkage.

The term “optionally substituted” as used herein means an optionalsubstitution of one to three, preferably one or two groups independentlyselected from halo, hydroxy, oxo, cyano, nitro, phenyl, benzyl,triazole, tetrazole, 4,5-dihydrothiazole, C₁–C₆ alkyl, C₁–C₄ haloalkyl,C₁–C₆ alkoxy, COR²², CONR²²R²², CO₂R²², NR²²R²², NR²²COR²³, NR²²SO₂R²³,OCOR²³, OCO₂R²², OCONR²²R²², SR²², SOR²³, SO₂R²³ and SO₂(NR²²R²²), whereR²² is independently at each occurrence H, C₁–C₆ alkyl, phenyl or benzyland R²³ is independently at each occurrence C₁–C₆ alkyl, phenyl orbenzyl.

The terms “heterocycle” and “heterocyclic” represent a stable,saturated, partially unsaturated, fully unsaturated or aromatic 5 or 6membered ring, said ring having from one to four heteroatoms that areindependently selected from the group consisting of sulfur, oxygen, andnitrogen. The heterocycle may be attached at any point which affords astable structure. Representative heterocycles include 1,3-dioxolane,4,5-dihydrooxazole, furan, imidazole, imidazolidine, isothiazole,isoxazole, morpholine, oxadiazole, oxazole, oxazolidinedione,oxazolidone, piperazine, piperidine, pyrazine, pyrazole, pyrazoline,pyridazine, pyridine, pyrimidine, pyrrole, pyrrolidine, tetrazole,thiadiazole, thiazole, thiophene and triazole. Representative“benzofused” heterocycles include benzoxazole, benzimidazole,benzofuran, benzothiophene, benzothiazole, azaindole, and indole.Further specific examples of benzofused and non-benzofused heterocyclesare described below in the Preparations and Examples sections.

The term “suitable solvent” refers to any solvent, or mixture ofsolvents, inert to the ongoing reaction that sufficiently solubilizesthe reactants to afford a medium within which to effect the desiredreaction.

The term “patient” includes human and non-human animals such ascompanion animals (dogs and cats and the like) and livestock animals.Livestock animals are animals raised for food production. Ruminants or“cud-chewing” animals such as cows, bulls, heifers, steers, sheep,buffalo, bison, goats and antelopes are examples of livestock. Otherexamples of livestock include pigs and avians (poultry) such aschickens, ducks, turkeys and geese. Yet other examples of livestockinclude fish, shellfish and crustaceans raised in aquaculture. Alsoincluded are exotic animals used in food production such as alligators,water buffalo and ratites (e.g., emu, rheas or ostriches).

The preferred patient of treatment is a human.

The terms “treating” and “treat”, as used herein, include theirgenerally accepted meanings, i.e., preventing, prohibiting, restraining,alleviating, ameliorating, slowing, stopping, or reversing theprogression or severity of a pathological condition, or sequela thereof,described herein.

The terms “preventing”, “prevention of”, “prophylaxis”, “prophylactic”and “prevent” are used herein interchangeably and refer to reducing thelikelihood that the recipient of a compound of formula I will incur ordevelop any of the pathological conditions, or sequela thereof,described herein.

As used herein, the term “effective amount” means an amount of acompound of formula I that is capable of treating conditions, ordetrimental effects thereof, described herein or that is capable ofagonizing the β₃ receptor.

The term “selective β₃ receptor agonist” means a compound that displayspreferential agonism of the β₃ receptor over agonism of the β₁ or β₂receptor. Thus, β₃ selective compounds behave as agonists for the β₃receptor at lower concentrations than that required for similar agonismat the β₁ and β₂ receptors. A β₃ selective compound also includescompounds that behave as agonists for the β₃ receptor and as antagonistsfor the β₁ and β₂ receptors.

The term “pharmaceutical” when used herein as an adjective meanssubstantially non-deleterious to the recipient patient.

The term “formulation”, as in pharmaceutical formulation, is intended toencompass a product comprising the active ingredient(s) (compound offormula I), and the inert ingredient(s) that make up the carrier, aswell as any product which results, directly or indirectly, fromcombination, complexation or aggregation of any two or more of theingredients, or from dissociation of one or more of the ingredients, orfrom other types of reactions or interactions of one or more of theingredients. Accordingly, the pharmaceutical formulations of the presentinvention encompass any composition made by admixing a compound of thepresent invention and a pharmaceutical carrier.

The term “unit dosage form” refers to physically discrete units suitableas unitary dosages for human subjects and other non-human animals (asdescribed above), each unit containing a predetermined quantity ofactive material calculated to produce the desired therapeutic effect, inassociation with a suitable pharmaceutical carrier.

Because certain compounds of the invention contain an acidic moiety(e.g., carboxy), the compound of formula I may exist as a pharmaceuticalbase addition salt thereof. Such salts include those derived frominorganic bases such as ammonium and alkali and alkaline earth metalhydroxides, carbonates, bicarbonates, and the like, as well as saltsderived from basic organic amines such as aliphatic and aromatic amines,aliphatic diamines, hydroxy alkamines, and the like.

Because certain compounds of the invention contain a basic moiety (e.g.,amino), the compound of formula I can also exist as a pharmaceuticalacid addition salt. Such salts include the salicylate, sulfate,pyrosulfate, bisulfate, sulfite, bisulfite, phosphate,mono-hydrogenphosphate, dihydrogenphosphate, metaphosphate,pyrophosphate, chloride, bromide, iodide, acetate, propionate,decanoate, caprylate, acrylate, formate, isobutyrate, heptanoate,propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate,maleate, 2-butyne-1,4 dioate, 3-hexyne-2,5-dioate, benzoate,chlorobenzoate, hydroxybenzoate, methoxybenzoate, phthalate,xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate,citrate, lactate, hippurate, β-hydroxybutyrate, glycolate, maleate,tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate,naphthalene-2-sulfonate, mandelate and like salts. Preferred acidaddition salts include the hydrochloride and glycolate salts.

Preferred Compounds of the Invention

Certain compounds of the invention are particularly interesting and arepreferred.

The following listing sets out several groups of preferred compounds. Itwill be understood that each of the listings may be combined with otherlistings to create additional groups of preferred compounds.

a) the bond represented by a dashed line is a double bond;

b) m is 0 or 1;

c) m is 0;

d) A¹, A² and A³ are carbon;

e) D is NH;

f) Het is at the ortho-position relative to X;

g) Het is an optionally substituted 5-membered, non-benzofused ring;

h) Het is selected from benzothiophene; furan; isoxazole; oxazole;pyrrole; tetrazole and thiophene; wherein said Het moieties areoptionally substituted once with methyl, cyano, SO₂NH₂ or COCH₃;

i) Het is pyrrol-1-yl;

j) Het is thien-2-yl optionally substituted once with methyl, cyano,SO₂NH₂ or COCH₃;

k) Het is thien-2-yl optionally substituted once with cyano, SO₂NH₂ orCOCH₃;

l) Het is thien-2-yl;

m) R¹ is H, methyl, ethyl, CF₃, chloro or fluoro;

n) R¹ is H, methyl, chloro or fluoro;

o) R¹ is H or fluoro;

p) R¹ is H;

q) R² is H, methyl, ethyl, CF₃, chloro or fluoro;

r) R² is H, methyl, chloro or fluoro;

s) R² is H or fluoro;

t) R²is H;

u) R³is H;

v) R⁴is H;

w) R⁵ forms a bond with X²;

x) R⁶ is cyano at each occurrence;

y) R⁷ is at the 6- or 7-position of the indole, benzofuran orbenzothiophene ring system to which it is attached;

z) R⁷ is at the 7-position;

aa) R⁷ is H or CO₂H;

bb) R⁷ is CH═CHR¹¹; R¹¹ is tetrazole, CONR¹⁶R¹⁶ or CO₂R¹⁶; and R¹⁶ isindependently H or C₁–C₄ alkyl at each occurrence;

cc) R⁷ is CH₂CH₂R¹¹, R¹¹ is CO₂R¹⁶ or CONR¹⁶R¹⁶, and R¹⁶ isindependently H or C₁–C₄ alkyl at each occurrence;

dd) R⁷ is CH₂CH₂R¹¹, R¹¹ is 1,2,3,4-tetrazole or phenyl substituted oncewith SO₂NR²²R²², and R²² is independently H or C₁–C₄ alkyl at eachoccurrence;

ee) R⁷ is thienyl substituted once with CO₂H or phenyl substituted oncewith CO₂H;

ff) R⁷ is OCH₂CONHSO₂(C₁–C₄ alkyl); OCH₂CH₂NHSO₂(C₁–C₄ alkyl); OCH₂CN;OCH₂CO₂R¹⁷; OCH₂CONR¹⁸R¹⁸; O(pyridine) wherein said pyridine moieity issubstituted once with cyano or CO₂H; OCH₂(tetrazole) orOCH₂(4,5-dihydrothiazole), and R¹⁷ and R¹⁸ are independently H or C₁–C₄alkyl at each occurrence;

gg) R⁷ is NHSO₂R¹⁰ and R¹⁰ is C₁–C₄ alkyl or phenyl;

hh) R⁷ is CH═CHR¹¹; R¹¹ is tetrazole or CO₂H;

ii) R⁷ is CH₂CH₂R¹¹ and R¹¹ is 1,2,3,4-tetrazole;

jj) R⁷ is OCH₂CN; OCH₂CO₂H; or OCH₂(tetrazole);

kk) R⁸ is H;

ll) X is OCH₂ and is connected through the 4-position of the indole ring(as shown in all of the exemplified compounds herein);

mm) X¹ is (CR¹⁹R²⁰)_(q) where R¹⁹ and R²⁰ are independently H or methylat each occurrence and q is 2;

nn) X¹ is C(CH₃)₂CH₂;

oo) X² is absent;

pp) the compound of formula I is an acid addition salt;

qq) the compound of formula I is the hydrochloride salt;

rr) the compound of formula I is the glycolate salt.

Synthesis

The compound of formula I may be prepared as described in the followingSchemes and Examples.

The reaction of Scheme 1 may be carried out under conditions appreciatedin the art for the amination of epoxides. For example, the epoxide offormula II may be combined with an amine of formula III in a loweralcohol, dimethylformamide, dimethylsulfoxide, or acetone, preferablyethanol, isopropanol, n-butanol or t-butanol, at room temperature to thereflux temperature of the reaction mixture, preferably between 40°C.–90° C. The reaction may also be carried out under conditionsgenerally described in Atkins, et al., Tet. Let., 27:2451, 1986. Theseconditions include mixing the reagents in the presence of trimethylsilylacetamide in a polar aprotic solvent such as acetonitrile,dimethylformamide, acetone, dimethylsulfoxide, dioxane, diethyleneglycol dimethyl ether, tetrahydrofuran, or other polar aprotic solventsin which the reagents are soluble.

The compound of formula I may also be prepared via a Suzuki couplingreaction as shown in Scheme 2.

A compound of formula IV may be reacted with a compound of formula IIIas described above in Scheme 1. The compound of formula V (an arylhalide) may then be reacted with a heteroaryl boronic acid, an arylboronic ester, or an aryl boronic cyclic ester, preferably an arylboronic acid, under conditions appreciated in the art for the couplingof aromatic halides with aryl boronic acids and their derivatives. Thiscoupling is known in the art generally as a Suzuki coupling. The skilledartisan will recognize that an aryl triflate may also be employed in thepresent Suzuki coupling as an alternative to employing an aryl halide.

The epoxide starting materials employed in Schemes 1 and 2 may beprepared by techniques recognized and appreciated by one skilled in theart. See, e.g., U.S. Pat. No. 4,663,334; European Patent Application171209; Korn, et al., J. Pharm. Sci., 69(9):1010–13, 1980 and referencescited below in the Preparations section for representative and/oranalogous procedures for preparing the epoxides of formula II and IV. Toillustrate, epoxides of formula II, where X is OCH₂ or SCH₂, may beprepared according to the procedure detailed in Scheme 3 wherein R¹⁹ isOH or SH and X′ is OCH₂ or SCH₂.

Equimolar amounts of a compound of formula VI and (2S)-(+)-glycidyl3-nitrobenzenesulfonate may be dissolved in an inert solvent such asacetone and treated with a slight excess of a weak base, such aspotassium carbonate. The suspension may then be heated at reflux for16–20 hours with stirring to provide a compound of formula II(a).Compounds of formula IV, where X is OCH₂ or SCH₂, may be prepared in ananalogous fashion.

The amines of formula III employed in Scheme 1 may also be prepared bytechniques recognized and appreciated by one skilled in the art. See,e.g., the Preparations below or the references cited therein forrepresentative and/or analogous procedures for preparing the amines offormula III.

Compounds of formula VI and Het-B(OH)₂ are either commerciallyavailable, known in the art, or can be prepared by methods known in theart or described herein.

Epoxides of Formula II and IV

Epoxides 1–21 and 23–30 are prepared as described below for use asdescribed in Scheme 1. Epoxide 22 and 31 are prepared as described belowfor use as described in Scheme 2. These epoxides are pictured below inTable 1.

TABLE 1

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31Epoxide 1

A mixture of 2-(thien-2-yl)phenol (J. Heterocycl. Chem., 22(6):1667–9,1985; 1 equivalent), (2S)-glycidyl 3-nitrobenzenesulfonate (1.2equivalents), potassium carbonate (1.2 equivalents) and acetone arerefluxed for 16 hours, cooled to room temperature and the solids removedvia filtration. The filtrate is concentrated and the crude productpurified on silica gel (ethyl acetate/hexane) to give the title epoxide.

Epoxide 5

A solution of 3-(dimethylamino)-1-(3-hydroxyphenyl)-2-propen-1-one (2.2g, 11.5 mmol) and hydroxylamine hydrochloride (1.17 g, 16.8 mmol) in 45ml dioxane/water 1:1 is heated for 2 hours at 60° C. The reaction ispoured into ice-water and the precipitate is collected by filtration,washed with water, and dried in vacuo to give 1.4 g of3-(5-isoxazolyl)phenol (75.5%). This phenolic product is reacted with(2S)-glycidyl 3-nitrobenzenesulfonate substantially as described forEpoxide 1 to give 1.33 g of the title epoxide (70%).

Epoxide 9

A mixture of 2-methoxybenzaldehyde (10.0 g, 73.4 mmol),tosylmethylisocyanide (14.34 g, 73.4 mmol) and potassium carbonate(10.14 g, 73.4 mmol) in 220 ml methanol is heated at reflux for 6 hours.The solvent is removed under reduced pressure and the residue pouredinto ice-water (800 ml). The precipitate is collected by filtration,washed with water, and dried in vacuo to give 9.05 g of5-(2-methoxyphenyl)oxazole (70%). Boron tribromide (1M indichloromethane, 36 ml) is added slowly to a cold solution (0° C.) ofthe above oxazole (3.0 g, 17.1 mmol) in dichloromethane (215 ml). Afterstirring overnight at room temperature, ice-water (50 ml) is addedcarefully. The aqueous layer is extracted with dichloromethane (50 ml),and the combined organic layers are dried over sodium sulfate andconcentrated under reduced pressure. The precipitate which formed afteraddition of dichloromethane (70 ml) is collected by filtration, heatedwith dichloromethane (15 ml), and filtered again to give 3.16 g of2-(5-oxazolyl)phenol. This phenolic product is reacted with(2S)-glycidyl 3-nitrobenzenesulfonate substantially as described forEpoxide 1 to give 400 mg of the title epoxide (9.5%).

Epoxide 11

A mixture of 2-bromo-1-(2-benzyloxyphenyl)ethanone (J. Med. Chem.,35:3045, 1992; 10.0 g, 32.77 mmol) and sodium formate (4.46 g, 65.6mmol) in dry dimethylformamide (100 ml) is stirred at room temperatureovernight. The mixture is poured into water (400 ml) and extracted withdichloromethane (2×100 ml). The combined extracts are dried over sodiumsulfate and concentrated under reduced pressure. The residue isdissolved in acetic acid (100 ml), treated with ammonium acetate (12.62g, 163.7 mmol), and the mixture is heated for 3 hours. After cooling,the mixture is diluted with water (400 ml) and extracted withdichloromethane (2×100 ml). The combined organic layers are washed withsaturated aqueous sodium bicarbonate solution (2×100 ml), dried oversodium sulfate, and concentrated in vacuo. 4-(2-Benzyloxyphenyl)oxazole(1.99 g, 24%) is obtained after chromatography (silica gel,dichloromethane).

To a solution of the oxazole from above (1.99 g, 7.92 mmol) indichloromethane (20 ml) is added 10% palladium on carbon (1.99 g). Themixture is put under an atmosphere of hydrogen, stirred at roomtemperature overnight, then filtered through Celite. The solvent isremoved under reduced pressure to give 1.15 g of 2-(oxazol-4-yl)phenol(90%).

The title epoxide (1.05 g, 72%) is prepared from the above phenol (1.08g, 6.7 mmol) and (2S)-glycidyl 3-nitrobenzenesulfonate substantially asdescribed for Epoxide 1.

Epoxide 12

Epoxide 12 is prepared from 2-methoxyphenylboronic acid and2-bromo-5-fluorothiophene; by a procedure substantially similar to thatdescribed for Epoxide 30.

Epoxide 13

To dioxane is added 3-methoxypyridyl-2-boronic acid (1 equivalent),2-bromothiophene (0.9 equivalents) and potassium carbonate. Palladium(0) tetrakistriphenylphoshine (0.03 equivalents) is then added and theresulting mixture is heated to 85° C. for 3 hours. The reaction iscooled to room temperature and poured into ethyl acetate and water. Theaqueous layer is extracted twice with ethyl acetate. The organicextracts are combined, and dried over sodium sulfate, concentrated andthe resulting residue is flash chromatographed in toluene/hexanes toafford 3-methoxy-2-(thien-2-yl)pyridine (90%).

The protected product from above is demethylated with pyridinehydrochloride neat at 200 degrees for 3 hours. The reaction is pouredinto ice/water and ethyl acetate is added. The layers are separated andthe organic layer is washed with water, dried over sodium sulfate andconcentrated. The resulting residue is flash chromatographed with ethylacetate/hexanes to afford 3-hydroxy-2-(thien-2-yl)pyridine (77%).3-Hydroxy-2-(thien-2-yl)pyridine is reacted with (2S)-glycidyl3-nitrobenzenesulfonate substantially as described for Epoxide 1 toyield the title epoxide.

Epoxide 14

Epoxide 14 is prepared from 2-(3-methylisoxazol-5-yl)phenol (J. Org.Chem. 49:4419, 1984) and (2S)-glycidyl 3-nitrobenzenesulfonate by aprocedure substantially similar to that described for Epoxide 1.

Epoxide 15

A solution of 5-bromothiophene-2-carbonitrile (1.25 g, 6.647 mmol) in 50ml of dioxane is degassed with argon.Tetrakis(triphenylphosphine)palladium(0) (768 mg, 0.665 mmol) is addedand the mixture stirred for 5 minutes. 2-Methoxybenzene boronic acid(2.02 g, 13.3 mmol) and 13.3 ml of aqueous 2 N sodium carbonate aresuccessively added and the mixture is stirred for 16 hours at 85° C.Extractive work-up (2×50 ml dichloromethane and 2×30 ml water). Organicphase is dried over sodium sulfate, filtered and evaporated. The residue(4.05 g) is purified via flash column on silica (eluent: 100%hexane>hexane/ethyl acetate 96:4 gradient to give 1.37 g of2-(5-cyanothien-2-yl)anisole (96%). MS=215 (M+).

An intimate mixture of 2-(5-cyanothien-2-yl)anisole (1.2 g, 5.9 mmol)and pyridinium hydrochloride (13.7 g, 119 mmol) is heated for 1 hour to210° C. under argon. The mixture is cooled to ambient temperature and a1:1 mixture of water and ethyl acetate is added to break and dissolvethe solid cake formed during the reaction. The slurry is thentransferred to a separation funnel and dichloromethane is added untilthe organic phase had a higher density than the water phase (organicphase=lower phase). The organic phase contains the desired product andis separated. The remaining aqueous phase is additionally extractedtwice with dichloromethane and the collected organic phases are driedover sodium sulfate and evaporated. The residue is purified via flashcolumn on silica (eluent: 100% hexane>hexane/ethyl acetate 8:2 gradient)to give 973 mg of 2-(5-cyanothien-2-yl)phenol (87%). M+=201.

To a solution of 2-(5-cyanothien-2-yl)phenol (970 mg, 4.82 mmol) in 20ml of dry 2-butanone is added (2S)-glycidyl 3-nitrobenzenesulfonate(1.25 g, 4.82 mmol) and potassium carbonate (732 mg, 5.301 mmol)successively. After stirring for 48 hours at 75° C., the mixture isdiluted with ethyl acetate and extracted with 2N aqueous sodiumhydroxide (2×30 ml) and water (1×30 ml). The title epoxide is directlyused without additional purification (M+=257).

Epoxides 16–20

Epoxides 16–20 are prepared by a procedure substantially similar to thatdescribed for Epoxide 15. The starting halogeno thiophenes used toprepare Epoxides 15–20 are known from the literature, see e.g., J.Mater. Chem., 5(4), 653–61, 1995; J. Chem. Soc., Perkin Trans. 2,5:625–30, 1982; Chem. Scr., 5(5), 217–26, 1974; Bull. Soc. Chim. Fr.,11:4115–20, 1967; Bull. Soc. Chim. Fr., 11:4121–6, 1967; Bull. Inst.Chem. Res., 52(3):561–5, 1974; J. Med. Chem., 43(16):3168–3185, 2000;Bioorg. Med. Chem. Lett., 10(5):415–418, 2000; and JP 08311060.

Epoxide 21

2-Thienyl-1-methoxybenzene (10 g, 53 mmol) is cooled to −78° C. in drytetrahydrofuran (265 ml) under nitrogen while stirring. n-Butyl lithiumin hexanes (1.6M, 37 ml, 59 mmol, 1.1 eq.) is added slowly and theresulting mixture is stirred cold for an hour. Chloromethyl formate (4.1ml, 53 mmol, 1.0 eq.) is added and the reaction is stirred cold foranother hour. The mixture is allowed to warm to room temperature beforequenching with saturated bicarbonate solution and ethyl acetate. Thelayers are separated and the organic phase is washed with brine, driedover sodium sulfate and concentrated. The residue is purified via flashchromatography in 5% ethyl acetate/hexanes to afford 7.9 g of2-(5-methoxycarbonylthien-2-yl)-1-methoxybenzene (61%).

2-(5-Methoxycarbonylthien-2-yl)-1-methoxybenzene is demethylated and theresulting phenol is reacted with (2S)-glycidyl 3-nitrobenzenesulfonateto prepare the title epoxide by the procedures described for Epoxide 1.

Epoxide 22

To a solution of 2-fluoro-6-iodoanisole (Justus Liebigs, Ann. Chem.,746:134, 1971; 4.31 g, 17.1 mmol) in dichloromethane (35 ml) is added a1M solution of borontribromide in dichloromethane (18.2 ml). The mixtureis kept under argon and stirred for 4 hours at room temperature. Themixture is poured into a saturated aqueous sodium bicarbonate solutionand the aqueous layer is extracted with ethyl acetate. The combinedorganic extracts are dried over sodium sulfate and concentrated underreduced pressure to give 2-fluoro-6-iodophenol (4.2 g).

The title epoxide (4.44 g, 86%) is prepared from 2-fluoro-6-iodophenoland (2S)-glycidyl 3-nitrobenzenesulfonate substantially as described forEpoxide 1 except using butanone as solvent.

Epoxides 24 and 25

To a solution of 6-fluorochroman-4-one (21.0 g, 126 mmol) in acetic acid(105 ml) is added bromine (6.5 ml, 126 mmol) at such a rate as to notraise the temperature above 25° C. After the addition is complete, thereaction is allowed to stir for 2 hours before pouring into 1 liter ofice. The resulting mixture is stirred overnight. The precipitate whichformed is filtered and placed in drying oven to produce 21 g of3-bromo-6-fluorochroman-4-one.

The product from (14 g, 57 mmol) above is dissolved in triethylamine(100 ml) and is stirred at reflux for 2 hours. The reaction is cooledand concentrated, taken up in chloroform, washed with 2N aqueoushydrochloric acid and water. The organic layer is dried over sodiumsulfate and concentrated. The product residue is crystallized from hotethyl acetate.

The product from above (6-fluorochromen-4-one (5.25 g, 32.0 mmol) andhydroxylamine hydrochloride (4.65 g, 67.2 mmol) are dissolved in ethanol(180 ml) and the resulting mixture is heated to reflux. The reaction isallowed to stir for 18 hours before cooling and concentrating. Theresidue is taken up in toluene and filtered to give 690 mg of4-fluoro-2-isoxazol-5-yl-phenol and from the filtrate 594 mg of4-fluoro-2-isoxazol-3-yl-phenol.

4-Flouro-2-isoxazol-3-yl-phenol and 4-fluoro-2-isoxazol-5-yl-phenol areseparately reacted with (2S)-glycidyl 3-nitrobenzenesulfonatesubstantially as described for Epoxide 1 to yield the title epoxides.

Epoxide 27

2-(3-Formyl-1-pyrrolyl)phenol (3 g, 16 mmol) and triethylamine (17.6mmol) are added to a suspension of hydroxylamine hydrochloride (1.22 g,17.6 mmol) in acetic anhydride (7.7 ml) and is allowed to stir overnightat ambient temperature. The mixture is refluxed for 5 hours,concentrated, dissolved in 50 ml ethanol and stirred for 10 minutes with50 ml 2 M aqueous sodium hydroxide. After neutralisation with aqueoushydrochloric acid, and extraction with ethyl acetate, the organic layeris dried and concentrated. The residue is purified by chromatography(toluene/ethanol 9:1) to yield 2.4 g of 2-(3-cyano-1-pyrrolyl)phenol(92%). This phenolic product is reacted with (2S)-glycidyl3-nitrobenzenesulfonate substantially as described for Epoxide 1 toyield the title epoxide.

Epoxide 28

A slurry of 2-cyano phenol (25 g, 209.87 mmol), triethylaminehydrochloride (43.3 g, 314.81 mmol), and sodium azide (20.5 g, 314.81mmol) in toluene (200 mL) is heated to the reflux temperature of themixture and then the mixture is allowed to stir at reflux for 15 hours.The mixture is cooled and washed with water (200 mL). The aqueous layeris washed with ether (100 mL), made acidic with concentrated HCl, andthe resulting solid is collected by filtration. The solid is washedtwice with water (200 mL) and dried under vacuum at 100° C. for 15 hoursto give 33.05 g of 2-(tetrazol-3-yl)phenol (97%).

2-(Tetrazol-3-yl)phenol (32.8 g, 202.3 mmol) is dissolved indimethylformamide (100 mL) and water (25 mL) and cooled in ice. Sodiumhydroxide (8.49 g, 212.3 mmol) in water (20 mL) is added and thesolution is warmed to ambient temperature. After thirty minutes,iodomethane (31.58 g, 222.5 mmol) is added neat. The solution is stirredfor 15 hours then diluted with ethyl acetate (300 mL) and water (500mL). The aqueous layer is washed three times with ethyl acetate (300 mL)and the organic layers are combined, washed three times with water (1L), once with brine (1.2 L), dried over magnesium sulfate, filtered andconcentrated in vacuo. The solid is purified by flash columnchromatography (80% hexane:20% ethyl acetate gradient to 50% hexane:50%ethyl acetate as an eluent) to give 23.5 g of2-(1-methyltetrazol-3-yl)phenol (66%).

2-(1-Methyltetrazol-3-yl)phenol (0.25 g, 1.54 mmol), (S)-glycidylnosylate (0.42 g, 1.62 mmol), and potassium carbonate (0.45 g, 3.23mmol) is dissolved in methyl ethyl ketone (2 mL), the mixture is heatedto the reflux temperature of the mixture, and then is allowed to stir atreflux for 15 hours. The slurry is cooled, filtered and concentrated invacuo. The solid is purified by flash column chromatography (80%hexane:20% ethyl acetate gradient to 50% hexane:50% ethyl acetate as aneluent) to give 270 mg (75%) of the title epoxide. FDMS m/e=233 (M⁺+1).

Epoxide 29

A 25 ml 1-propanol solution of 2-methoxyphenyl boronic acid (1.2 g, 7.5mmol) and 5-bromothien-2-ylsulfonamide (1.2 g, 5 mmol) is stirred underN₂ at room temperature. Palladium(II) acetate (56 mg, 0.25 mmol),triphenylphosphine (200 mg, 0.75 mmol), 2M aqueous Na₂CO₃ (3 ml, 6mmol), and 7 ml H₂O are added and the resulting mixture is refluxed(˜88° C.) for 1 hour. The reaction is cooled, diluted with ethylacetate, washed with brine, and the brine back extracted with ethylacetate. The extracts are combined, washed with aqueous NaHCO₃, brine,dried (Na₂SO₄), filtered, and the filtrate is concentrated. The residueis purified by chromatography (SiO₂, ethyl acetate/hexane gradient) togive 943 mg (70%) of 5-(2-methoxyphenyl)thiophene-2-sulfonamide.

A 70 ml CH₂Cl₂ suspension of 5-(2-methoxyphenyl)thiophene-2-sulfonamide(1.0 g, 3.7 mmol) is stirred under N₂ at −75° C. as boron tribromide(1.1 ml, 12 mmol) is syringed into the reaction mixture. The ambersolution is stirred for 30 minutes at −75° C., then at 0° C. for 2–3hours. The reaction is quenched with ice, extracted with CH₂Cl₂. Theextracts are washed with brine, dried (Na₂SO₄), filtered, and thefiltrate is concentrated. The residue is purified by chromatography(SiO₂, ethyl acetate/hexane gradient) to give 720 mg of5-(2-hydroxyphenyl)thiophene-2-sulfonamide (76%).

5-(2-Hydroxyphenyl)thiophene-2-sulfonic acid amide (1.8 g, 7.1 mmol),K₂CO₃ (1.1 g, 8.5 mmol), and (2S)-glycidyl 3-nitrobenzenesulfonate (2.1g, 7.8 mmol) are reacted as described for the preparation of Epoxide 1to give 1.5 g of the title epoxide (70%).

Epoxide 30

A solution of 3-bromothiophene (978 mg, 6 mmol) in 50 ml of dioxane isdegassed with argon. Tetrakis-(triphenylphosphine)-palladium(0) (700 mg,0.6 mmol) is added and the mixture is stirred for 5 minutes.2-Methoxybenzene boronic acid (1.824 g, 12 mmol) and 12 ml of aqueous 2N sodium carbonate are successively added and the resulting mixture isstirred for 16 hours at 85° C. The mixture is allowed to cool to roomtemperature then is extracted with dichloromethane (2×50 ml). Theorganic extracts are washed with water (2×30 ml) then dried over sodiumsulfate, filtrated and evaporated. The residue is purified via flashcolumn on silica (eluent: hexane/ethyl acetate 99:1 gradient to give2-(thien-3-yl)anisole.

An intimate mixture of 2-(thien-3-yl)anisole (1.2 g, 4 mmol) and 6.0 g(50 mmol) of pyridinium hydrochloride is heated for 20 minutes to 200°C. (1000 W MW, microwave). The mixture is allowed to cool to roomtemperature then is extracted with ethyl acetate and dichloromethane.The organic extracts are washed with water, dried over sodium sulfateand evaporated. The residue is purified via flash column on silica(eluent: 100% hexane>hexane/ethyl acetate 9:1 gradient) to give 700 mgof 2-(thien-3-yl)phenol (97%). M+=176.

To a solution of 2-(thien-3-yl)phenol (700 mg, 4 mmol) in 20 ml of dry2-butanone is added s(−) glycidyl nosylate (1.03 g, 4 mmol) andpotassium carbonate (605 mg, 4.4 mmol) successively. After stirring for16 hours at 80° C. the mixture is diluted with ethyl acetate andextracted with 2N aqueous sodium hydroxide (2×30 ml) and water (1×30ml). The residue is purified via flash column on silica (eluent:DCM/hexane 8:2>1/1 gradient) to give 689 mg of the title epoxide(74.7%). M+=232.

Epoxide 31

A mixture of 2-iodophenol (5.00 g, 22.7 mmol), (2S)-glycidyl3-nitrobenzenesulfonate (5.89 g, 22.7 mmol) and potassium carbonate(3.44 g, 24.9 mmol) in methylethylketone (150 ml) is refluxed for 18hours. After cooling, the salts are removed by filtration. The filtercake is rinsed thoroughly with dichloromethane and the collectedfiltrates are evaporated. The residue is purified via flashchromatography on silica gel using a hexane-hexane/ethyl acetategradient (100 to 90:10).

Epoxides 2–4, 6–8, 10, 23 and 26

2-(Thiazol-2-yl)phenol (Arnold, et al., WO 94/22846);2-(pyrrol-1-yl)phenol (J. Het. Chem., 8:283–287, 1971);2-(isoxazol-3-yl)phenol (J. Het. Chem., 8:283–287, 1971);2-(isothiazol-5-yl)phenol (J. Chem. Res. (S), 349, 1988; J. Chem. Res.(S), 163, 1992); 2-(1,3,4-thiadiazol-2-yl)phenol (WO 94/22846);2-(oxazol-2-yl)phenol (WO 94/22846); 2-(furan-3-yl)phenol (Ger. Offen.DE2914166); 2-thiazol-4-yl-phenol (WO 94/22846); and2-(1,2,3-thiadiazol-2-yl)phenol (WO 94/22846); are reacted with(2S)-glycidyl 3-nitrobenzenesulfonate substantially as described forEpoxide 1 to yield the title epoxides.

Amines of Formula III

Amines 1–88 are prepared as described below or are obtained fromcommercial sources for use as described in Schemes 1 or 2. These aminesare pictured below in Table 2.

TABLE 2

1

2

3

4

5

6

7

8a

8b

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

36

37

38

39

40

41

42

43

44

45

46

47

48

49

50

51

52

53

54

55

56

57

58

59

60

61

62

63

64

65

66

67

68

69

70

71

72

73

74

75

76

77

78

79

80

81

82

83

84

85

86

87

88Amine 1

A mixture of 7-benzyloxy gramine (1.99 g, 7.10 mmol), solid NaOH (298mg, 7.22 mmol) and 2-nitropropane (4.5 mL, 50 mmol) is heated to reflux.After 10 minutes at reflux, a thick slurry developed which is difficultto stir. Gas evolution is observed, and an additional 1 mL of2-nitropropane is added to loosen the mixture. After 29 hours, themixture is allowed to cool to ambient temperature. Ether (30 mL) isadded and the mixture is filtered. The filtrate is treated with 10%acetic acid (6 mL), the layers are separated and the organic layer isrinsed with water (2×25 mL). The organic layer is dried (Na₂SO₄) andconcentrated to give 2.12 g of3-(2-methyl-2-nitropropyl)-7-(benzyloxy)indole (92%). MS (ES+) m/z 325.

A mixture of 3-(2-methyl-2-nitropropyl)-7-(benzyloxy)indole (25.0 g,77.1 mmol), Raney Nickel® (9.5 g wet lump), and 3A ethanol (250 mL) ispressurized to 50 psig with H₂ and is heated to 60° C. After 1 hour, themixture is cooled to ambient temperature. The mixture is diluted withtetrahydrofuran (100 mL) and is warmed to 50° C. The catalyst is removedby filtration and the cake is rinsed with 50° C. tetrahydrofuran (4×50mL). The filtrate is concentrated to a solid which is dried in a 50° C.vacuum oven to provide 22.41 (99%) of2-methyl-1-[7-(benzyloxy)indol-3-yl]prop-2-ylamine. MS (ES+) m/z 295(100%).

Solid di-tert-butyl dicarbonate (20 g, 92 mmol) is added to a slurry of2-methyl-1-[7-(benzyloxy)indol-3-yl]prop-2-ylamine (31.54 g, 107.1mmol), triethylamine (16.5 mL, 118 mmol) and CH₂Cl₂ (300 mL) at ambienttemperature; within 2 hours the slurry became a homogeneous solution.After 23.5 hours, the solution is poured into water (200 mL), and thelayers are separated. The organic layer is extracted with 0.5 M NaHSO₄(200 mL), and the combined aqueous layers are rinsed with CH₂Cl₂ (125mL). The combined organic layers are rinsed with 50% saturatedNaCl/saturated NaHCO₃ (300 mL), dried (Na₂SO₄), filtered andconcentrated. The resulting residue is purified by flash chromatographywith CH₂Cl₂ followed by 5% ethyl acetate/CH₂Cl₂ to provide 25 g of[2-(7-benzyloxy-1H-indol-3-yl)-1,1-dimethyl-ethyl]-carbamic acidtert-butyl ester (70%). MS (ES−) m/z 393 (100%).

A mixture of [2-(7-benzyloxy-1H-indol-3-yl)-1,1-dimethyl-ethyl]-carbamicacid tert-butyl ester (20.75 g, 52.6 mmol), 5% Pd/C (1.00 g, 5 wt %),and 3A ethanol (200 mL) is pressurized to 55 psig with H₂, and is heatedto 50° C. After 40 minutes, the slurry is filtered, and the filtrate isconcentrated to give 15.41 g of[2-(7-hydroxy-1H-indol-3-yl)-1,1-dimethyl-ethyl]-carbamic acidtert-butyl ester (96%). FDMS m/e=305 (M⁺+1).

To a solution of[2-(7-hydroxy-1H-indol-3-yl)-1,1-dimethyl-ethyl]-carbamic acidtert-butyl ester (6.04 g, 19.8 mmol) in dichloromethane (125 mL) isadded triethylamine (14 mL, 99.2 mmol). The mixture is cooled to 0° C.and trifluoromethanesulfonyl anhydride (4.4 mL, 25.8 mmol) is addeddropwise as a solution in dichloromethane (25 mL). The mixture is warmedto ambient and stirred overnight. The solution is diluted with brine andextracted three times with dichloromethane. The combined organics aredried over anhydrous sodium sulfate then filtered and evaporated. Theresidue is purified using silica gel chromatography (hexane/20% ethylacetate in hexane gradient elution) to give 7.199 g oftrifluoro-methanesulfonic acid3-(2-tert-butoxycarbonylamino-2-methyl-propyl)-1H-indol-7-yl ester(83%). FDMS m/e=437 (M⁺+1).

A solution of 4-bromobenzamide (150 mg, 0.75 mmol),bis(pinacolato)diboron (209 mg, 0.825 mmol), potassium acetate (0.221 g,2.25 mmol) and {1,1′-bis(diphenylphosphino)-ferrocene} dichloropalladiumdichloromethane complex (18 mg, 0.0225 mmol) in dimethylsulfoxide (5 mL)is heated to 80° C. for two hours. The mixture is cooled to 20° C. andtrifluoro-methanesulfonic acid3-(2-tert-butoxycarbonylamino-2-methyl-propyl)-1H-indol-7-yl ester (262mg, 0.600 mmol), {1,1′-bis(diphenylphosphino)-ferrocene}dichloropalladium dichloromethane complex (18 mg, 0.0225 mmol) andsodium carbonate (1.9 mL, 2M, 3.75 mmol) are added. The mixture isheated to 80° C. overnight. The mixture is diluted with brine and ethylacetate. The organic fraction is washed seven times with brine, thendried over anhydrous sodium sulfate, filtered and evaporated. Theresidue is purified using silica gel chromatography (dichloromethane/10%methanol, 0.7M ammonia in dichloromethane gradient elution) to give 143mg of{2-[7-(4-carbamoyl-phenyl)-1H-indol-3-yl]-1,1-dimethyl-ethyl}-carbamicacid tert-butyl ester (58%). FDMS m/e=408 (M⁺+1).

To a solution of{2-[7-(4-carbamoyl-phenyl)-1H-indol-3-yl]-1,1-dimethyl-ethyl}-carbamicacid tert-butyl ester (333 mg, 0.817 mmol) in dioxane (5 mL) at 0° C. isadded hydrochloric acid (4 mL, 4M solution in dioxane, 16 mmol). Themixture is stirred at 0° C. for three hours and then warmed to ambientfor three hours. The mixture is diluted with saturated sodiumbicarbonate and then extracted three times with ethyl acetate. Thecombined organics are dried over anhydrous sodium sulfate, filtered andthen the solvent is removed in vacuo to give 208 mg of the titlecompound (83%). FDMS m/e=308 (M⁺+1).

Amine 2

To a solution of trifluoro-methanesulfonic acid3-(2-tert-butoxycarbonylamino-2-methyl-propyl)-1H-indol-7-yl ester (305mg, 0.699 mmol) in tetrahydrofuran (4.5 mL) is added sodium carbonate (1mL, 2M, 2 mmol), tetrakis(triphenylphosphine)-palladium (32 mg, 0.0280mmol) and 4-trifluoromethylbenzeneboronic acid (0.199 g, 1.05 mmol). Themixture is refluxed for 22 hours, then cooled, diluted with brine andextracted three times with ethyl acetate. The combined organics aredried over anhydrous sodium sulfate, filtered and then evaporated invacuo. The residue is purified using silica gel chromatography(hexane/20% ethyl acetate, hexane gradient elution) to give 282 mg of{1,1-dimethyl-2-[7-(4-trifluoromethyl-phenyl)-1H-indol-3-yl]-ethyl}-carbamicacid tert-butyl ester (93%). FDMS m/e=433 (M⁺+1).

The title amine is prepared from{1,1-dimethyl-2-[7-(4-trifluoromethyl-phenyl)-1H-indol-3-yl]-ethyl}-carbamicacid tert-butyl ester as described above for Amine 1 (205 mg, 99%). FDMSm/e=333 (M⁺+1).

Amine 3

To a solution of trifluoro-methanesulfonic acid3-(2-tert-butoxycarbonylamino-2-methyl-propyl)-1H-indol-7-yl ester (340mg, 0.779 mmol) in dimethylformamide (5 mL) is added triethylamine (0.14mL, 1.01 mmol), tetrakis(triphenylphosphine)-palladium (36 mg, 0.0312mmol) and 3-thiopheneboronic acid (130 mg, 1.01 mmol). The mixture isrefluxed for 22 hours, then cooled and diluted with brine and ethylacetate. The organic phase is washed 7 times with brine. The organicsare dried over anhydrous sodium sulfate, filtered and then evaporated invacuo. The residue is purified using silica gel chromatography(hexane/20% ethyl acetate, hexane gradient elution) to give 198 mg of[1,1-dimethyl-2-(7-thiophen-3-yl-1H-indol-3-yl)-ethyl]-carbamic acidtert-butyl ester (69%). FDMS m/e=371 (M⁺+1).

The title amine is prepared from[1,1-dimethyl-2-(7-thiophen-3-yl-1H-indol-3-yl)-ethyl]-carbamic acidtert-butyl ester as described above for Amine 1 (132 mg, 95%). FDMSm/e=271 (M⁺+1).

Amine 4

To a solution of trifluoro-methanesulfonic acid3-(2-tert-butoxycarbonylamino-2-methyl-propyl)-1H-indol-7-yl ester (437mg, 1.00 mmol) in dimethylformamide (6 mL) is added triethylamine (0.18mL, 1.30 mmol), tetrakis(triphenylphosphine)-palladium (46 mg, 0.0401mmol) and 2-thiopheneboronic acid (167 mg, 1.30 mmol). The mixture isrefluxed for 22 hours, then cooled and diluted with brine and ethylacetate. The organic phase is washed 7 times with brine. The organicsare dried over anhydrous sodium sulfate, filtered and then evaporated invacuo. The residue is purified using silica gel chromatography(hexane/20% ethyl acetate, hexane gradient elution) to give 116 mg of[1,1-Dimethyl-2-(7-thiophen-2-yl-1H-indol-3-yl)-ethyl]-carbamic acidtert-butyl ester (31%). FDMS m/e=371 (M⁺+1).

The title amine is prepared from[1,1-Dimethyl-2-(7-thiophen-2-yl-1H-indol-3-yl)-ethyl]-carbamic acidtert-butyl ester as described above for Amine 1 (120 mg, 95%). FDMSm/e=271 (M⁺+1).

Amine 5

To a solution of trifluoro-methanesulfonic acid3-(2-tert-butoxycarbonylamino-2-methyl-propyl)-1H-indol-7-yl ester (262mg, 0.600 mmol) in dimethylformamide (3.5 mL) is added triethylamine(0.11 mL, 0.780 mmol), tetrakis(triphenylphosphine)-palladium (28 mg,0.0240 mmol) and 2,4-bistrifluoromethylbenzeneboronic acid (201 mg,0.780 mmol). The mixture is heated to 100° C. for 20 hours, then cooled,diluted with brine and ethyl acetate. The organics are washed seventimes with brine then dried over anhydrous sodium sulfate, filtered andevaporated in vacuo. The residue is purified using silica gelchromatography (hexane/20% ethyl acetate, hexane gradient elution) togive 268 mg of{2-[7-(2,4-Bis-trifluoromethyl-phenyl)-1H-indol-3-yl]-1,1-dimethyl-ethyl}-carbamicacid tert-butyl ester (89%). FDMS m/e=501 (M⁺+1).

The title amine is prepared from{2-[7-(2,4-Bis-trifluoromethyl-phenyl)-1H-indol-3-yl]-1,1-dimethyl-ethyl}-carbamicacid tert-butyl ester as described above for Amine 1 (208 mg, 100%).FDMS m/e=401 (M⁺+1).

Amines 6 and 7

A mixture of [2-(7-hydroxy-1H-indol-3-yl)-1,1-dimethyl-ethyl]-carbamicacid tert-butyl ester (15.55 g, 51.1 mmol), bromoacetonitrile (10.7 mL,153 mmol), K₂CO₃ (17.78 g, 128.6 mmol) and 2-butanone is heated toreflux. After 1 hour the mixture is allowed to cool and is filteredthrough celite. The filtrate is concentrated to an oil which is purifiedby flash chromatography with CH₂Cl₂ followed by 5% ethyl acetate/CH₂Cl₂to give 15.18 g of[2-(7-cyanomethoxy-1H-indol-3-yl)-1,1-dimethyl-ethyl]-carbamic acidtert-butyl ester (86%). MS (ES−) m/z 342.

To a solution of[2-(7-cyanomethoxy-1H-indol-3-yl)-1,1-dimethylethyl]-carbamic acidtert-butyl ester in 20 ml dry ethanol is added 2 ml 10% HCl in ethanoland the mixture is stirred at room temperature for 2 days. The solventis evaporated, the residue re-dissolved in ethanol and loaded on a SCXcolumn. After washing with ethanol the product is eluted with 10% NH₃ inethanol, evaporated and purified on a silica column eluting withCH₂Cl₂/10% NH₃ in ethanol from 99/1 to 90/10, to yield 231 mg of Amine 6(34%) and 213 mg of Amine 7 (26%).

Alternate Preparation for Amine 6

To solution of[2-(7-cyanomethoxy-1H-indol-3-yl)-1,1-dimethyl-ethyl]-carbamic acidtert-butyl ester (1.0 g, 2.85 mmol) in dioxane (5.0 mL) at 0° C. isadded 4 N HCl (3.0 mL). The reaction mixture is allowed to continue for1 hour at 0° C. and warmed to room temperature. The reaction mixture isevaporated to dryness, the resulting residue is taken up with water(25.0 mL), and saturated NaHCO₃ (5.0 mL) is added. This aqueous mixtureis extracted with ethyl acetate (2×50 mL). The combined organic extractsare washed with brine and dried (Na₂SO₄). Evaporated to dryness give 590mg of the title amine (86%). FDMS m/e=244.1 (M⁺+1).

Amines 8a and 8b

Phosphorous oxychloride (252 mL, 2.7 mol) is added dropwise over 15minutes to precooled dimethylformamide (−10° C.) (1800 mL) whilemaintaining the temperature below −5° C. and the resulting solution isstirred for 1 hour at −10 to 0° C. A solution of 7-benzyloxyindole (502g, 2.25 mmol) in dimethylformamide (900 mL) is added dropwise whilemaintaining the temperature below 0° C. The cooling is removed and theresulting mixture is allowed to warm to room temperature and stir for 1hour. After cooling to 0° C., 5 N NaOH (4.5 L) is added over 20 minutesat 0° C. to 5° C. The resulting mixture is heated at reflux for 30minutes. Upon cooling to 10° C., the product precipitates. Afterstirring for 20 minutes, the product is filtered, washed thoroughly withwater (4×1.5 L) and vacuum dried at 40° C. to give 574.5 g of7-benzyloxy-3-carbanal-1H-indole (101.6%).

The crude aldehyde from above (570 g, 2.25 mol), ammonium acetate(173.4, 2.25 mol) and nitroethane (661.8 g, 8.8 mol) are added toxylenes (1.35 L). The heterogeneous mixture is heated at reflux under aDean-Stark trap with 4A molecular sieves in the sleeve for 30 minuteswithout reflux return and 45 minutes with reflux return to remove water.When the reaction is complete the mixture is cooled to room temperatureover 1 hour and is then cooled to 0° C. for 30 minutes. The solidproduct is collected by filtration and is washed sequentially withxylenes (1 L), water (1 L), and xylenes (1 L). Vacuum drying overnightat 40° C. affords 610 g (88%) of7-benzyloxy-3-(2-nitroprop-1-enyl)-1H-indole (nitroolefin).

Lithium aluminum hydride (LAH, 24 g, 600 mmol) is added portionwise todry tetrahydrofuran (1800 mL) at −5° C. to 5° C. A solution of thenitroolefin from above (61.6 g, 200 mmol) in tetrahydrofuran (1200 mL)is added to the LAH solution over 30 minutes while maintaining thetemperature at −5° C. to 5° C. When the addition is complete, thereaction mixture is allowed to warm to 30° C. over 1.5 hours and isstirred at 25° C. to 35° C. for 2 hours. To complete the reaction, themixture is heated to 60° C. for 30 minutes. After cooling to 0° C., thereaction is quenched by the sequential addition of water (30 mL), 5 NNaOH (30 mL), and water (100 mL) and the resulting mixture is stirredover the weekend. The aluminum salts are removed by filtration and thecake rinsed with tetrahydrofuran (500 mL). The combined filtrates areconcentrated to give 47.6 g (55% purity corrected yield, approx 65%pure) of 7-benzyloxy-3-(2-aminopropyl)-1H-indole.

To 7-benzyloxy-3-(2-aminopropyl)-1H-indole (45.6 g, 65% pure, 102 mmol)is added dichloromethane (450 mL) and triethylamine (18.1 g, 179 mmol)to give a slurry. t-Butyloxycarbonyl anhydride (35.5 g, 163 mmol) isadded portionwise to the mixture over 5 minutes and is rinsed into theflask with dichloromethane (50 mL). Carbon dioxide gas is evolved andthe temperature increases from 23° C. to 31° C. Within 1 hour thereaction is complete and the solution is washed sequentially with 1 NHCl, water, and 10% saturated sodium chloride solution. The crudeproduct is purified by silica gel chromatography (500 g silica gel)eluting with dichloromethane followed by 5% ethylacetate/dichloromethane. Crystallization of the product containingfractions from ethyl acetate/hexanes affords 33.9 g (86% yield) of{1-methyl-2-[7-(benzyloxy)-1H-indol-3-yl]ethyl}-carbamic acid tert-butylester.

{1-Methyl-2-[7-(benzyloxy)-1H-indol-3-yl]ethyl}-carbamic acid tert-butylester (38.9 g, 102 mmol) is added to a slurry of 5% Pd/carbon (3.89 g of50% water wet catalyst) in ethanol denatured with toluene (389 mL). Theresulting mixture is pressurized with hydrogen (50 psig) and is heatedto 50° C. while shaking in a Paar™ hydrogenation apparatus. The reactionis complete after 3 hours, the catalyst is removed by filtration and thesolvent is removed by rotary evaporation to afford a nearly quantitativeyield of the oxygen-sensitive{1-methyl-2-[7-hydroxy-1H-indol-3-yl]ethyl}-carbamic acid tert-butylester. The phenol is used immediately in the next step withoutpurification.

The crude {1-methyl-2-[7-hydroxy-1H-indol-3-yl]ethyl}-carbamic acidtert-butyl ester from above (29.2 g, 102 mmol theory) is dissolved inmethyl ethyl ketone (300 mL) and bromoacetonitrile (20.4 mL, 306 mmol)and potassium carbonate (33.8 g, 250 mmol) is added. The mixture isheated at 80° C. for 2 hours. The solids are removed by filtration, thecake is washed with methyl ethyl ketone, and the combined filtrates areconcentrated by rotary evaporation. The crude product is purified byflash chromatography (500 g silica gel, eluted with 8×500 mLdichloromethane, 4×500 mL 5% ethyl acetate/dichloromethane, 6×500 mL 10%ethyl acetate/dichloromethane). The fractions containing product areconcentrated and hexane is added to the solution to precipitate out theproduct affording 23.7 g (70.2% yield) of racemic{1-methyl-2-[7-cyanomethoxy-1H-indol-3-yl]ethyl}-carbamic acidtert-butyl ester.

The two enantiomeric compounds that make up racemic{1-methyl-2-[7-cyanomethoxy-1H-indol-3-yl]ethyl}-carbamic acidtert-butyl ester are separated by preparative chiral chromatography inquantitative yield. Analytical chromatographic conditions: ChiralPak AD(4.6 mm×250 mm), 60% 3A ethanol, 40% heptane, 1 mL/min, 245 nm.

To a solution of(R)-{1-methyl-2-[7-cyanomethoxy-1H-indol-3-yl]ethyl}-carbamic acidtert-butyl ester (1.2 mmol) in 10 ml dry ethanol is added 1 ml 10% HClin ethanol and the mixture is stirred at room temperature for 2 days.The solvent is evaporated, the residue re-dissolved in ethanol andloaded on a SCX column. After washing with ethanol the product is elutedwith 10% NH₃ in ethanol and evaporated to yield 220 mg of Amine 8a (80%)as a colourless oil. Amine 8b is prepared from(S)-{1-methyl-2-[7-cyanomethoxy-1H-indol-3-yl]ethyl}-carbamic acidtert-butyl ester by a procedure substantially similar to that describedfor amine 8a.

Amine 9

To a solution of[2-(7-cyanomethoxy-1H-indol-3-yl)-1,1-dimethyl-ethyl]-carbamic acidtert-butyl ester (2.8 mmol) in 10 ml dry dioxane is added 1 mlconcentrated HCl and the mixture is stirred at room temperatureovernight. The solvent is evaporated, the residue re-dissolved inethanol and loaded on a SCX column. After washing with ethanol theproduct is eluted with 10% NH₃ in ethanol and evaporated to yield 667 mgof Amine 9 (91%).

Amine 10

To a solution of Amine 8b (1.4 mmol) in 5 ml dry dioxane is added 0.5 mlconcentrated HCl and the mixture is stirred at room temperatureovernight. The solvent is evaporated, the residue re-dissolved inethanol and loaded on a SCX column. After washing with ethanol theproduct is eluted with 10% NH₃ in ethanol and evaporated to yield 320 mgof Amine 10 (92%).

Amine 11

Amine 11 is prepared according to the literature procedure detailed inJ. Med. Chem., 23:285–289, 1980.

Amine 12

To a solution of[2-(7-Hydroxy-1H-indol-3-yl)-1,1-dimethyl-ethyl]-carbamic acidtert-butyl ester (274 mg, 0.900 mmol) in dimethylformamide (15 mL) isadded sodium hydride (26 mg, 1.07 mmol). The mixture is stirred atambient temperature for 25 minutes under nitrogen.2-Chloro-nicotinonitrile (187 mg, 1.35 mmol) is added and the mixture isheated in an oil bath to eighty degrees Celsius for 15 hours, undernitrogen. Water (50 ml) is added to quench the reaction and the mixtureis extracted three times with 50 mL of ethyl acetate. The organic layersare combined and washed twice with 50 mL of 1.00 N sodium hydroxide. Theorganic layer is dried with sodium sulfate, filtered and the solventevaporated. The residue is dissolved in dichloromethane and purifiedusing silica gel chromatography (6% 2M ammonia in methanol, 94%dichloromethane used as mobile phase) to give 350 mg (96%) of{2-[7-(3-cyano-pyridin-2-yloxy)-1H-indol-3-yl]-1,1-dimethyl-ethyl}-carbamicacid tert-butyl ester. FDMS m/e=407 (M⁺+1).

{2-[7-(3-Cyano-pyridin-2-yloxy)-1H-indol-3-yl]-1,1-dimethyl-ethyl}-carbamicacid tert-butyl ester (119 mg, 0.293 mmol) is dissolved in 10 mL of 1,4dioxane. The mixture is cooled to zero degrees Celsius in an ice/waterbath. To the mixture is added 10 mL of 4N hydrochloric acid in 1,4dioxane, and the resulting mixture is stirred at zero degrees, undernitrogen, for five hours. The solvent is evaporated, and the residue istaken up in water. The pH of the water is adjusted to 9 using sodiumbicarbonate, and is extracted three times with 50 mL of ethyl acetate.The organic layers are combined, dried with sodium sulfate, filtered,and the solvent removed in vacuo to give 218 mg of the title amine(83%). FDMS m/e=307 (M⁺+1).

Amines 13 and 14

The title amines are prepared from[2-(7-hydroxy-1H-indol-3-yl)-1,1-dimethyl-ethyl]-carbamic acidtert-butyl ester and 2-chloro-isonicotinonitrile and[2-(7-hydroxy-1H-indol-3-yl)-1,1-dimethyl-ethyl]-carbamic acidtert-butyl ester and 6-chloro-nicotinonitrile, respectively, asdescribed for the preparation of Amine 12.

Amine 15

To a solution of[2-(7-hydroxy-1H-indol-3-yl)-1,1-dimethyl-ethyl]-carbamic acidtert-butyl ester (104 mg, 0.342 mmol) in dimethylformamide (10 mL) isadded sodium hydride (10 mg, 0.410 mmol). The mixture is stirred atambient temperature for 30 minutes under nitrogen. 6-Chloro-nicotinicacid methyl ester (99 mg, 0.581 mmol) is added and the mixture is heatedin an oil bath to eighty degrees Celsius for 15 hours, under nitrogen.The mixture is then heated an additional 5 hours at eighty-five degreesCelsius. Water (100 ml) is added to quench the reaction and the mixtureis extracted three times with 50 mL of ethyl acetate. The organic layersare combined and washed twice with 50 mL of 1.00 N sodium hydroxide. Theorganic layer is dried with sodium sulfate, filtered and the solventevaporated. The residue is dissolved in dichloromethane and purifiedusing silica gel chromatography (6% 2M ammonia in methanol, 94%dichloromethane used as mobile phase) to give 87 mg (58%) of6-[3-(2-tert-butoxycarbonylamino-2-methyl-propyl)-1H-indol-7-yloxy]-nicotinicacid methyl ester. FDMS m/e=440 (M⁺+1).

6-[3-(2-tert-Butoxycarbonylamino-2-methyl-propyl)-1H-indol-7-yloxy]-nicotinicacid methyl ester (87 mg, 0.198 mmol) is dissolved in 5 mL of 1,4dioxane. The mixture is cooled to zero degrees Celsius in an ice/waterbath. To the mixture is added 15 mL of 4N hydrochloric acid in 1,4dioxane, and the mixture is stirred at zero degrees, under nitrogen, forfive hours. The solvent is evaporated, and the residue is taken up inwater. The pH of the water is adjusted to 10 using sodium bicarbonate,and is extracted three times with 50 mL of ethyl acetate. The organiclayers are combined, dried with sodium sulfate, filtered, and thesolvent removed in vacuo to give 24 mg of the title amine (36%). FDMSm/e=340 (M⁺+1).

Amine 16

The title amine is prepared from3-(bromomethyl)-5-chlorobenzo[B]thiophene in a similar fashion asdescribed in U.S. Pat. No. 4,321,398.

Amine 17

3-Methylbenzo[b]thiophene (9.9 g, 67 mmol) is heated in carbontetrachloride (133 ml) to near reflux in the presence ofn-bromosuccinimide (11.9 g, 67 mmol, 1.0 eq.).2,2′Azobisisobutyronitrile (2.2 g, 13.3 mmol, 0.2 eq.) is added and theresulting mixture is refluxed for two hours. After cooling, the reactionmixture is filtered through a glass-fritted funnel, and the filtrate isconcentrated. The residue is triturated with petroleum ether and tolueneto afford 6.42 g of 3-Bromomethylbenzo[b]thiophene (42%).

The title amine is prepared from 3-(bromomethyl)-benzo[B]thiophene in asimilar fashion as described in U.S. Pat. No. 4,321,398.

Amine 18

The title amine is prepared from 3-(Bromomethyl)benzofuran (J. Med.Chem., 40(17):2706–2725, 1997) in a similar fashion as described in U.S.Pat. No. 4,321,398.

Amine 19

A mixture of 2,3-dihydro-1H-indole (5.74 g, 48.2 mmol), and(S)-propylene oxide (2.8 g, 48.2 mmol) in ethanol (200 mL) is heated atreflux for 18 hours. The resulting mixture is cooled to roomtemperature, and evaporated to give a crude oil. The material ispurified by flash chromatography (25% ethyl acetate/hexanes) to give5.37 g (63%) of 2,3-dihydro-1-(2-hydroxypropyl)indole.

To a solution of 2,3-dihydro-1-(2-hydroxypropyl)indole (4.87 g, 27.5mmol) in CH₂Cl₂ (150 mL) at 0° C., is added triethylamine (19.1 mL,137.4 mmol), followed by methanesulfonyl chloride (4.24 mL, 54.9 mmol).The reaction is quenched after 10 minutes by addition of saturatedNaHCO₃ solution. The reaction mixture is extracted with CH₂Cl₂, driedover MgSO₄ and evaporated. This crude material is taken up indimethylformamide (150 ml), sodium azide added (3.57 g, 54.9 mmol), andthe reaction mixture heated at 70° C. for 7 hours. Diethyl ether andwater is added to the cooled reaction mixture, and the water layerextracted several times with diethyl ether. The organic extracts arecombined, washed with brine several times, dried over Na₂SO₄, andconcentrated. The residue is purified by flash chromatography (15% ethylacetate/hexanes) to give 4.44 g (80%) of2,3-dihydro-1-(2-azidopropyl)indole.

2,3-Dihydro-1-(2-azidopropyl)indole (3.93 g, 19.5 mmol) andtriphenylphosphine (6.38 g, 24.3 mmol) is dissolved in tetrahydrofuran(350 mL) and water (526 microliters, 29.2 mmol) is added. The reactionmixture is heated at reflux for 8 hours, cooled to room temperature, andconcentrated. This crude residue is diluted with methanol, and passedover a cation exchange column to remove the excess triphenyl phosphineand byproducts. Flash chromatography (90:10:1 CH₂Cl₂/methanol/NH₄OH)provides the 1.05 g of the title amine (31%).

Amine 20

To a mixture of Boc-L-alanine (5 g, 24.4 mmol), indoline (3.2 ml, 29mmol), and N,N-diisopropylethylamine (9.2 mL, 53 mmol) indimethylformamide (130 mL) is added EDC (6.1 g, 32 mmol) andhydroxybenzotriazole (3.9 g, 29 mmol). The resulting mixture is stirredat room temperature overnight. The mixture is partitioned between ethylacetate and H₂O. The aqueous phase is extracted with ethyl acetate, andthe combined organic phases are washed with brine, dried (MgSO₄), andconcentrated. The residue is purified by trituration with hexane to give6.1 g of the Boc-protected title amine (80%).

To a mixture of the Boc-protected amine from above (4.0 g, 13.8 mmol) inCH₂Cl₂ (20 mL) at 0° C. is added trifluoroacetic acid (5 mL). Additionaltrifluoroacetic acid (5 mL) is added after 1 hour and 2 hours. After 2.5hours, the mixture is neutralized with a saturated aqueous solution ofNaHCO₃. The aqueous phase is extracted with CH₂Cl₂ (2×), and thecombined organic phases are dried (MgSO₄) and concentrated to provide2.0 g (77%) of the title amine.

Amine 21

The title amine is prepared from Boc-D-alanine (5 g, 24.4 mmol) andindoline (3.2 ml, 29 mmol) by a procedure substantially similar to thatdescribed above for Amine 20.

Amine 22

To a solution of[2-(7-cyanomethoxy-1H-indol-3-yl)-1,1-dimethyl-ethyl]-carbamic acidtert-butyl ester (3.8 mmol) is added 2 N NaOH (10.0 mL, 20 mmol). Thereaction mixture is reluxed for 2 hours. The reaction mixture is cooledto room temperature, evaporated to about 10 mL, acidified to pH 3.0 with1 N HCl. The mixture is extracted with ethyl acetate (2×50 mL), thecombined organic layer washed with brine and dried (Na₂SO₄). Evaporationto dryness afford[3-(2-tert-butoxycarbonylamino-2-methyl-propyl)-1H-indol-7-yloxy]-aceticacid (1.3 g, 95%). FDMS m/e=363.2 (M⁺+1).

To a solution of[3-(2-tert-butoxycarbonylamino-2-methyl-propyl)-1H-indol-7-yloxy]aceticacid (480 mg, 1.32 mmol) in dimethylformamide (5.0 mL) is added methylamine (1.52 mL, 1.0 M in tetrahydrofuran, 1.52 mmol) and Bop reagents(670 mg, 1.52 mmol). The reaction mixture is stirred at room temperaturefor 3 hours before evaporation to dryness. The resulting residue ischromatographed (30% ethyl acetate/hexane) to give 500 mg of[1,1-dimethyl-2-(7-methylcarbamoylmethoxy-1H-indol-3-yl)-ethyl]-carbamicacid tert-butyl ester (75%). FDMS m/e=375.1 (M⁺+1).

The title amine is prepared from[1,1-dimethyl-2-(7-methylcarbamoylmethoxy-1H-indol-3-yl)-ethyl]-carbamicacid tert-butyl ester as described for the alternate preparation ofAmine 6 (66%). FDMS m/e=276.1 (M⁺+1).

Amine 23

Trifluoro-methanesulfonic acid3-(2-tert-butoxycarbonylamino-2-methyl-propyl)-1H-indol-7-yl ester (200mg, 0.46 mmol), methyl acrylate (80 mg, 0.92 mmol) and triethylamine(0.40 mL, 3.0 mmol) is stirred in dimethylformamide (2.0 mL) at roomtemperature for 30 minutes. Dichlorobis(triphenylphosphine)palladium (31mg, 0.045 mmol) is added, the reaction mixture is heated to 90° C. andallowed to stir overnight. The reaction is cooled to room temperature,poured into a separatory funnel containing ethyl acetate and brine (50mL each) and the aqeous layer is extracted with ethyl acetate (50 mL).The combined organic layers are washed with brine, dried (Na₂SO₄) andevaporated. The residue is purified using silica gel chromatography (20%ethyl acetate/hexane) to give 140 mg of3-[3-(2-tert-butoxycarbonylamino-2-methyl-propyl)-1H-indol-7-yl]-acrylicacid methyl ester (82%). FDMS m/e=372.2 (M⁺+1).

The title compound is prepared from3-[3-(2-tert-butoxycarbonylamino-2-methyl-propyl)-1H-indol-7-yl]-acrylicacid methyl ester as described for the alternate preparation of Amine 6(82%). FDMS m/e=277.2 (M⁺+1).

Amine 24

3-[3-(2-tert-Butoxycarbonylamino-2-methyl-propyl)-1H-indol-7-yl]-propionicacid methyl ester is prepared from3-[3-(2-tert-butoxycarbonylamino-2-methyl-propyl)-1H-indol-7-yl]-acrylicacid methyl ester as described below for the preparation of{2-[7-(2-methanesulfonyl-ethyl)-1H-indol-3-yl]-1,1-dimethyl-ethyl}-carbamicacid tert-butyl ester (80%). FDMS m/e=375.2 (M⁺+1).

The title amine is prepared from3-[3-(2-tert-Butoxycarbonylamino-2-methyl-propyl)-1H-indol-7-yl]-propionicacid methyl ester as described for the alternate preparation of Amine 6(100%).

Amine 25

3-[3-(2-tert-Butoxycarbonylamino-2-methyl-propyl)-1H-indol-7-yl]-acrylamideis prepared from[1,1-dimethyl-2-(7-trifluoromethanesulfonylmethyl-1H-indol-3-yl)-ethyl]-carbamicacid tert-butyl ester and acrylamide as described for the preparation ofAmine 23 (98%). FDMS m/e=356.2 (M⁺+1).

The title amine is prepared from3-[3-(2-tert-butoxycarbonylamino-2-methyl-propyl)-1H-indol-7-yl]-acrylamideas described for the alternate preparation of Amine 6 (83%). FDMSm/e=258.2 (M⁺+1).

Amine 26

{2-[7-(2-Carbamoyl-ethyl)-1H-indol-3-yl]-1,1-dimethyl-ethyl}-carbamicacid tert-butyl ester is prepared from3-[3-(2-tert-butoxycarbonylamino-2-methyl-propyl)-1H-indol-7-yl]-acrylamideas described for the preparation of Amine 28 (100%). FDMS m/e=360.2(M⁺+1).

The title amine is prepared from{2-[7-(2-carbamoyl-ethyl)-1H-indol-3-yl]-1,1-dimethyl-ethyl}-carbamicacid tert-butyl ester as described for the alternate preparation ofAmine 6 (98%). FDMS m/e=260.2 (M⁺+1).

Amine 27

{2-[7-(2-Methanesulfonyl-vinyl)-1H-indol-3-yl]-1,1-dimethyl-ethyl}-carbamicacid tert-butyl ester is prepared from[1,1-dimethyl-2-(7-trifluoromethanesulfonylmethyl-1H-indol-3-yl)-ethyl]-carbamicacid tert-butyl ester and methyl vinyl sulfone as described for thepreparation of Amine 23 (98%). FDMS m/e=392.2 (M⁺+1).

The title amine is prepared from{2-[7-(2-methanesulfonyl-vinyl)-1H-indol-3-yl]-1,1-dimethyl-ethyl}-carbamicacid tert-butyl ester as described for the alternate preparation ofAmine 6 (80%). FDMS m/e=293.2 (M⁺+1).

Amine 28

To a solution of{2-[7-(2-methanesulfonyl-vinyl)-1H-indol-3-yl]-1,1-dimethyl-ethyl}-carbamicacid tert-butyl ester (0.40 g, 1.02 mmol) in methanol (20.0 mL) is added10% Pd/C (0.10 g) in methanol (2.0 mL). The reaction mixture is purgedwith hydrogen and hydrogenation is carried out with a hydrogen balloonovernight. The reaction mixture is filtered and the filtrate isevaporated to dryness to give 320 mg of{2-[7-(2-methanesulfonyl-ethyl)-1H-indol-3-yl]-1,1-dimethyl-ethyl}-carbamicacid tert-butyl ester (80%). FDMS m/e=395.2 (M⁺+1).

The title amine is prepared from{2-[7-(2-methanesulfonyl-ethyl)-1H-indol-3-yl]-1,1-dimethyl-ethyl}-carbamicacid tert-butyl ester as described for the alternate preparation ofAmine 6 (92%). FDMS m/e=295.2 (M⁺+1).

Amine 29

{2-[7-(2-Cyano-vinyl)-1H-indol-3-yl]-1,1-dimethyl-ethyl}-carbamic acidtert-butyl ester is prepared from[1,1-dimethyl-2-(7-trifluoromethanesulfonylmethyl-1H-indol-3-yl)-ethyl]-carbamicacid tert-butyl ester and acrylonitrile as described for the preparationof Amine 23 (85%). FDMS m/e=339.2 (M⁺+1).

The title amine is prepared from{2-[7-(2-Cyano-vinyl)-1H-indol-3-yl]-1,1-dimethyl-ethyl}-carbamic acidtert-butyl ester as described for the alternate preparation of Amine 6(94%). FDMS m/e=240.2 (M⁺+1).

Amine 30

{2-[7-(2-Cyano-ethyl)-1H-indol-3-yl]-1,1-dimethyl-ethyl}-carbamic acidtert-butyl ester is prepared from{2-[7-(2-cyano-vinyl)-1H-indol-3-yl]-1,1-dimethyl-ethyl}-carbamic acidtert-butyl ester as described for the preparation of Amine 28 (86%).FDMS m/e=341.2 (M⁺+1).

The title amine is prepared from{2-[7-(2-Cyano-ethyl)-1H-indol-3-yl]-1,1-dimethyl-ethyl}-carbamic acidtert-butyl ester as described for the alternate preparation of Amine 6(86%). FDMS m/e=242.2 (M⁺+1).

Amine 31

{1,1-Dimethyl-2-[7-(2-[1,2,4]triazol-1-yl-vinyl)-1H-indol-3-yl]-ethyl}-carbamicacid tert-butyl ester is prepared from[1,1-dimethyl-2-(7-trifluoromethanesulfonylmethyl-1H-indol-3-yl)-ethyl]-carbamicacid tert-butyl ester and 1-vinyl-1,2,4-triazole as described for thepreparation of Amine 23 (93%). FDMS m/e=381.2 (M⁺+1).

The title amine is prepared from{1,1-dimethyl-2-[7-(2-[1,2,4]triazol-1-yl-vinyl)-1H-indol-3-yl]-ethyl}-carbamicacid tert-butyl ester as described for the alternate preparation ofAmine 6 (56%). FDMS m/e=282.2 (M⁺+1).

Amine 32

(1-Methyl-1H-indol-3-yl)-acetonitrile (J. Org. Chem., 63:6053–6058,1998) is converted to1-(1-methyl-1H-indol-3-yl)-cyclopentanecarbonitrile and then saidcarbonitrile compound is converted to the title amine via proceduresdescribed in Eur. J. Med. Chem., 31:123–132, 1996.

Amine 34

To a vigorously stirred solution of 2-bromo-4,6-difluoro aniline (100 g,0.48 mol) in pyridine (400 mL), at 0° C., is added ethyl chloroformate(70 ml, 0.73 mol) at a rate to keep the temperature below 5° C. Whenaddition is complete, the mixture is stirred at 0° C.–5° C. anadditional 2 hours while monitoring by TLC (20% ethyl acetate/hexane,UV). The reaction is then allowed to warm to room temperature, filteredand the filtrate concentrated. The residue is dissolved in diethylether/ethyl acetate (500 ml/250 ml) and washed with H₂O, 2.5 N HCl,aqueous NaHCO₃, brine, dried (Na₂SO₄), filtered, concentrated, andtriturated with petroleum ether to give 126 g of2-bromo-4,6-difluoro-N-carbethoxy aniline (94%).

In a 2L flask, 2-bromo-4,6-difluoro-N-carbethoxy aniline (42 g, 150mmol) in CH₃CN (500 mL) is degassed with vacuum and purged with N₂.Dichlorobis(triphenylphosphine)palladium(II) (10.5 g, 15 mmol, 10 mol%), followed by CuI (710 mg, 4 mmol, 2.5 mol %) and triethyl amine (41mL) are added and rinsed in with 100 mL of CH₃CN. Trimethylsilylacetylene (31.8 ml, 225 mmol) is added and reaction is refluxed underN₂. Approximately 2 hours later, the starting material is consumed,indicated by TLC (20% ethyl acetate/hexane, UV). The reaction is cooled,filtered, concentrated, and the residue is dissolved in ethyl acetate,washed with H₂O, brine, dried (Na₂SO₄), filtered, concentrated, and ispurified by flash chromatography (SiO₂, ethyl acetate/hexane gradient)to yield 30 g of2-(trimethylsilylethynyl)-4,6-difluoro-N-carbethoxyaniline (71%).

Fresh sodium ethoxide is prepared by carefully adding NaH (16 g of 60%oil dispersion, 400 mmol) to 550 mL of ethanol under N₂.2-(Trimethylsilylethynyl)-4,6-difluoro-N-carbethoxyaniline (28 g, 100mmol) in 150 mL of ethanol is added and reaction is stirred at roomtemperature approximately 45 minutes, while monitoring by TLC (20% ethylacetate/hexane, UV) until all the starting material is consumed. Themixture is heated to reflux and monitored by TLC until the intermediatematerial is consumed (approx. 1 hour). Reaction is cooled to roomtemperature, concentrated, diethylether is added, washed with H₂O,brine, dried (Na₂SO₄), filtered, concentrated, and is purified by flashchromatography (SiO₂, ethyl acetate/hexane gradient) to yield 12 g of5,7-difluoro-indole (78%).

The 1.0 M ICl in CH₂Cl₂ (43 ml, 43 mmol) is added to a solution of5,7-difluoro-indole (6 g, 39 mmol) in 35 ml pyridine under N₂ at 0° C.and the resulting mixture is stirred for 30 minutes. The reaction isdiluted with toluene and washed with brine, 1N HCl, 1N NaOH, dried(Na₂SO₄), filtered and concentrated. The crude 3-iodo-5,7-difluoroindoleis stirred in toluene (85 ml) and 5 N NaOH (70 ml), tetrabutylammoniumbromide (1.25 g, 3.9 mmol), then benzenesulfonyl chloride (6.2 ml, 48mmol) are added and the resulting mixture is stirred 24 hours. The twophase reaction mixture is diluted with toluene, washed with brine, dried(Na₂SO₄), filtered, concentrated and the residue is triturated withdiethyl ether/petroleum ether. The resulting solid is filtered to give14.2 g of N-Benzenesulfonyl-3-iodo-5,7-difluoroindole (87%).

A 3.0 M diethyl ether solution of ethylmagnesium bromide (7.3 ml, 21.8mmol) is added under N₂ at 0° C. to a 95 ml tetrahydrofuran solution ofN-benzenesulfonyl-3-iodo-5,7-difluoro-indole (8.4 g, 20 mmol). Theresulting mixture is stirred for 20 minutes at 0° C., allowed to warm toroom temperature over 20 minutes, then recooled to 0° C. A 20 mltetrahydrofuran solution of (S) N,N dibenzyl-2-aminopropanal (Syn.Lett., 1997,2, 223–224, 5.1 g, 22 mmol) is added to the reaction mixtureand the resulting mixture is stirred 1 hour as it warmed to room temp.The reaction is quenched with aqueous NH₄Cl, extracted with ethylacetate, washed with brine, dried (Na₂SO₄), filtered, concentrated, andthe residue is purified by flash chromatography (SiO₂, ethylacetate/hexane gradient) to yield 8.4 g of2-(N,N-dibenzylamino)-1-(1-benzenesulfonyl-5,7-difluoro-1H-indol-3-yl)-propan-1-ol.(77%)

Lithium aluminum hydride (LAH) (0.7 g, 18 mmol) is added portionwise toa dioxane/tetrahydrofuran (90 ml/10 ml) solution of2-(N,N-dibenzylamino)-1-(1-benzenesulfonyl-5,7-difluoro-1H-indol-3-yl)-propan-1-ol(1.9 g, 3.3 mmol) under N₂ at 0° C. After the addition is complete, thereaction is allowed to warm to room temperature, then is refluxed for 1hour. The reaction is quenched with H₂O and 15% aqueous NaOH, filtered,and the filtrate is diluted with ethyl acetate, washed with brine, dried(Na₂SO₄), filtered, concentrated, and the residue is purified by flashchromatography (SiO₂, ethyl acetate/hexane gradient) to yield 1.2 g ofdibenzyl-[2-(5,7-difluoro-1H-indol-3-yl)-1(S)-methyl-ethyl]-amine (86%).

A 100 ml ethanol mixture ofdibenzyl-[2-(5,7-difluoro-1H-indol-3-yl)-1(S)-methyl-ethyl]-amine (930mg, 2.4 mmol), ammonium formate (1.5 g, 24 mmol), and 10% palladium oncharcoal (250 mg, 0.24 mmol) is reluxed 1 hour, cooled, filtered, andconcentrated. The residue is purified by flash chromatography using avariable mixture of 90:10:1 CH₂Cl₂/methanol/NH₄OH to give 420 mg of thetitle amine (83%).

Amine 35

The title amine is prepared fromN-benzenesulfonyl-3-iodo-5,7-difluoro-indole and (R) N,Ndibenzyl-2-aminopropanal by a procedure substantially similar to thatdescribed for Amine 34.

Amines 33 and 36

The title amines are prepared as described in J. Med. Chem.,40:2762–2769, 1997.

Amine 37

NaH (180 mg of 60% oil dispersion, 4.5 mmol) is added to a solution ofdibenzyl-[2-(5,7-difluoro-1H-indol-3-yl)-1(R)-methyl-ethyl]-amine (1.4g, 3.6 mmol) in 20 ml dimethylformamide under N₂ at 0° C. The resultingmixture is stirred for 20 minutes, then is allowed to warm to roomtemperature over 20 minutes. A 5 ml solution of iodomethane indimethylformamide (7.2 mmol) is added dropwise and the reaction mixtureis stirred for 1 hour. The reaction is quenched with cold aqueousNaHCO₃, xtracted with ethyl acetate, washed with brine, dried (Na₂SO₄),filtered, concentrated and is purified by flash chromatography (SiO₂,ethyl acetate/hexane gradient) to yield 1.3 g ofdibenzyl-[2-(5,7-difluoro-1-methyl-1H-indol-3-yl)-1(R)-methyl-ethyl]-amine(89%).

Dibenzyl-[2-(5,7-difluoro-1-methyl-1H-indol-3-yl)-1(R)-methyl-ethyl]-amine(1.23 g, 3 mmol) is deprotected in the same manner as Amine 34 to give500 mg of the title amine (76%).

Amine 38

POCl₃ (10.9 ml, 71 mmol) is added dropwise to 21 ml of dimethylformamideunder N₂ at 10–20° C., is stirred 15 minutes, then a 13 mldimethylformamide solution of 5-methoxy-6-fluoro-indole (J. Med. Chem.,22:63–69, 1979; 10.7 g, 64.7 mmol) is added at a rate to keep thereaction temperature between 10 and 20° C. After the addition iscomplete, the mixture is stirred for 1 hour. Crushed ice and aqeuousNaOH (12.5 g/50 ml H₂O) is added to reaction. The resulting mixture isheated to reflux with a heat gun for 1 minute, cooled to 10° C., and isfiltered to give 11.8 g of 6-fluoro-5-methoxy-1H-indole-3-carbaldehyde(95%).

A mixture of nitroethane (44 ml, 611 mmol),6-fluoro-5-methoxy-1H-indole-3-carbaldehyde (11.8 g, 61 mmol), andammonium acetate (1.78 g, 23 mmol) is stirred at 100° C. for 3 hours,allowed to cool, and is filtered to give 14 g of6-fluoro-5-methoxy-3-(2-nitro-propenyl)-1H-indole (92%).

A 45 ml tetrahydro solution of6-fluoro-5-methoxy-3-(2-nitro-propenyl)-1H-indole (2.83 g, 11.3 mmol) isadded dropwise to a 60 ml tetrahydrofuran suspension of LAH (2.14 g,56.5 mmol) at 0° C., and the resulting mixture is allowed to warm toroom temperature, then is refluxed for 1 hour. The reaction is quenchedwith H₂O and 15% aqueous NaOH, then is filtered, concentrated, and thefiltrate is diluted with ethyl acetate, washed with brine, dried(Na₂SO₄), filtered, concentrated, and the residue is purified by flashchromatography (90:10:1 CH₂Cl₂/methanol/NH₄OH) to give 1 g of the titleamine (41%).

Amine 39

A 0° C. solution of 4-hydroxyindole (20 g, 150 mmol) in 500 ml ofdimethylformamide is treated with NaH (60% dispersion in mineral oil;6.6 g, 165 mmol). After 30 minutes, bromoacetonitrile (11.5 ml, 165mmol) is added, and the resulting mixture is allowed to slowly warm toambient temperature and stir for 3 days. The reaction mixture is dilutedwith ethyl acetate and washed 3 times with H₂O. The organic layer isdried over Na₂SO₄ and concentrated in vacuo. The crude residue ispurified by normal phase HPLC (SiO₂; 5% step gradient of 0 to 20% ethylacetate in hexanes) to give 25 g of (1H-indol-4-yloxy)acetonitrile(97%).

A 0° C. solution of (1H-indol-4-yloxy)acetonitrile (5.93 g, 34.4 mmol)in 175 ml of tetrahydrofuran is treated with NaH (60% dispersion inmineral oil; 1.65 g, 41.3 mmol). After 1 hour, (S)-(−)-propylene oxide(4 g, 68.9 mmol) is added, and the resulting mixture is allowed toslowly warm to ambient temperature and stir for 3 days. The reactionmixture is quenched with H₂O and extracted with ethyl acetate. Theorganic layer is dried over Na₂SO₄ and concentrated in vacuo.Purification of the crude residue (SiO₂; 10% step gradient of 0 to 40%ethyl acetate in hexanes) affords 2.1 g of the alkylated product (26%).

A 0° C. solution of the alkylated product (1.8 g, 7.82 mmol) in 40 ml ofCH₂Cl₂ and 3.3 ml of triethylamine is treated with methanesulfonylchloride (1.2 ml, 15.6 mmol). After 1 hour, the reaction mixture isdiluted with ethyl acetate (100 ml) and 1M aqueous Na₂CO₃ solution (100ml). The organic layer is washed with brine, dried over Na₂SO₄ andconcentrated in vacuo. The crude mesylate is dissolved in 40 ml ofdimethylformamide, and NaN₃ (1.0 g, 15.6 mmol) is added. The resultingmixture is heated at 60° C. for 4.5 hours, then poured into H₂O (100 ml)and extracted with ethyl acetate (2×100 ml). The combined organicextracts are washed with brine (100 ml), dried over Na₂SO₄ andconcentrated in vacuo. The crude azide is dissolved in 25 ml oftetrahydrofuran and treated with triphenylphosphine (2.56 g, 9.78 mmol).After stirring at room temperature for 1 hour, the reaction mixture isheated at 60° C. for 3 hours. Water (10 ml) is added to hydrolyze theintermediate aza-ylide and heating is continued for an additional 3hours. Upon cooling to ambient temperature, the reaction mixture isdiluted with ethyl acetate (200 ml) and brine (200 ml). The organiclayer is washed with brine (100 ml), dried over Na₂SO₄ and concentratedin vacuo. Purification of the crude residue (SiO₂; 100% CHCl₃ then 2.5%2M NH₃/methanol in CHCl₃) affords 1.65 g (7.2 mmol; 92%) of the titleamine.

Amines 40 and 41

The title Amines are prepared from methyl indole-4-carboxylate andmethyl indole-5-carboxylate, respectively, substantially as describedfor Amine 39.

Amine 46

A 0° C. solution of indole (7 g, 59.8 mmol) in 200 ml ofdimethylformamide is treated with NaH (60% dispersion in mineral oil;3.1 g, 77.7 mmol). After 20 minutes, bromoacetonitrile (4.2 ml, 59.8mmol) is added, and the resulting mixture is allowed to slowly warm toambient temperature and stir overnight. The reaction mixture is dilutedwith ethyl acetate (500 ml) and washed with H₂O (3×200 ml). The organiclayer is dried over Na₂SO₄ and concentrated in vacuo. The crude residueis purified by flash chromatography (SiO₂; 5% then 20% ethyl acetate inhexanes) to give 2.53 g of indol-1-yl-acetonitrile (27%).

A solution of indol-1-yl-acetonitrile (2.5 g, 16 mmol) in 100 ml ofethanol and 15 ml of anhydrous NH₃ is treated with Raney nickel (300mg). The resulting mixture is heated for 8 hours (80° C.) under anatmosphere of H₂ (300 psi). The reaction mixture is filtered over celiteand concentrated in vacuo. Purification of the crude residue (SiO₂; 2%then 4% 2M NH₃/methanol in CHCl₃) affords 715 mg of the title amine(28%).

Amines 42, 43, 44 and 48

The title amines are prepared from 5-hydroxyindole,4-hydroxy-2-methylindole, indole and 6-hydroxyindole, respectively,substantially as described for Amine 39.

Amine 49

A slurry of 4-fluoro-3-(dimethylaminomethyl)-1H-indole (4.3 g, 22.4mmol) in 14.1 ml of 2-nitropropane is treated with solid NaOH (941 mg,23.5 mmol), and the resulting mixture is heated at reflux overnight.After cooling to ambient temperature, the reaction mixture is acidifiedwith 10% aqueous acetic acid (25 ml) and stirring is continued for 30minutes. The reaction mixture is diluted with ethyl acetate (50 ml) andbrine (50 ml). The layers are separated, and the organic layer is washedwith brine (50 ml), dried over Na₂SO₄ and concentrated in vacuo to give3.71 g of 4-fluoro-3-(2-methyl-2-nitropropyl)-1H-indole (76%).

A solution of 4-fluoro-3-(2-methyl-2-nitropropyl)-1H-indole (3.7 g, 17.0mmol) in 95 ml of ethanol and 70 ml of ethyl acetate is treated with 5%Pd/C (900 mg) and the resulting mixture is shaken for 6 hours at ambienttemperature under an atmosphere of H₂ (60 psi). Additional 5% Pd/C (900mg) is added, and the reaction mixture is re-subjected to H₂ at 60 psiwhile being heated overnight at 50° C. The reaction mixture is filteredover celite and concentrated in vacuo. Purification of the crude residue(SiO₂; 1% step gradient of 0 to 10% 2M NH₃/methanol in CHCl₃) affords1.16 g of the title amine (33%).

Amine 50

Amine 50 is prepared from 5-fluoro-3-(dimethylaminomethyl)-1H-indole ina method similar to that described for the preparation of Amine 49.

Amine 51

Methyl indole-4-carboxylate (7.0 g, 40 mmol) and Eschenmoser's salt(N,N-dimethylnethyleneammonium iodide; 7.8 g, 42 mmol) are combined in130 ml of acetic acid. After heating at 65° C. for 2 hours, the reactionmixture is concentrated in vacuo. The resulting solid is triturated withethyl acetate, filtered and dried in vacuo to give3-dimethylaminomethyl-1H-indole-4-carboxylic acid methyl esterhydroiodide in quantitative yield.

A 0° C. solution of 3-dimethylaminomethyl-1H-indole-4-carboxylic acidmethyl ester hydroiodide (19 g, 52.7 mmol) in 75 ml of methanol and 75ml of 2-nitropropane is treated with dimethyl sulfate (10 ml, 105.5mmol) and solid sodium methoxide (6.3 g, 110.6 mmol) sequentially. Theresulting mixture is allowed to warm to ambient temperature, and, afterstirring overnight, the reaction mixture is diluted with ethyl acetate(300 ml) and saturated aqueous NH₄Cl solution (500 ml). The aqueouslayer is extracted with ethyl acetate (200 ml), and the combined organiclayers are dried over Na₂SO₄ and concentrated in vacuo to give3-(2-methyl-2-nitropropyl)-1H-indole-4-carboxylic acid methyl ester inquantitative yield.

A solution of 3-(2-methyl-2-nitropropyl)-1H-indole-4-carboxylic acidmethyl ester (14.8 g, 53.6 mmol) in 70 ml of tetrahydrofuran and 70 mlof ethyl acetate is treated with Raney nickel (3.3 g) and the resultingmixture is heated overnight (60° C.) under an atmosphere of H₂ (60 psi).The reaction mixture is filtered over celite and concentrated in vacuo.Purification of the crude residue (SiO₂; 2.5% step gradient of 2.5 to20% 2M NH₃/methanol in CHCl₃) affords 9.21 g of the title amine (71%).

Amine 53

A solution of Amine 52 (1.0 g, 4.06 mmol) and NH₄Cl (800 mg, 15 mmol) in100 ml of methanol is charged with 5 ml of anhydrous NH₃. The resultingmixture is sealed in a bomb and heated at 150° C. for 40 hours. Thereaction mixture is cooled and concentrated in vacuo. The crude residueis purified by radial chromatography (SiO₂; 10% 2M NH₃/methanol inCHCl₃) to afford 344 mg of the title amine (37%).

Amine 55

A 0° C. solution of 1,2-diamino-2-methylpropane (650 ml, 6.21 mmol),indole-3-carboxylic acid (1.0 g, 6.21 mmol) andN,N-diisopropylethylamine (2.7 ml, 15.2 mmol) in 30 ml of CH₂Cl₂ istreated with 1-[3-dimethylamino)propyl]-3-ethylcarbodiimidehydrochloride (1.2 g, 6.21 mmol). The resulting mixture is allowed towarm to ambient temperature and stir overnight. The reaction mixture iswashed with H₂O, dried over Na₂SO₄ and concentrated in vacuo.Purification of the crude residue (SiO₂; 10% 2M NH₃/methanol in CHCl₃)affords 752 mg of the title amine (52%).

Amine 57

6-Fluoro-3-(2-methyl-2-nitropropyl)-1H-indole is prepared from6-fluoro-3-(dimethylaminomethyl)-1H-indole by a method similar to thatdescribed for Amine 49, paragraph 1.

A solution of 6-fluoro-3-(2-methyl-2-nitropropyl)-1H-indole (1.16 g,4.91 mmol) in 6 ml of tetrahydrofuran and 12 ml of methanol is treatedwith CuSO₄.5H₂O (400 mg, 1.35 mmol) and NaBH₄ (882 mg, 23.3 mmol). Theresulting mixture is stirred at ambient temperature for 30 minutes andthen diluted with H₂O (20 ml), CH₂Cl₂ (20 ml) and concentrated NH₄OH (5ml). After 1 hour, the layers are separated, and the organic layer isdried over Na₂SO₄ and concentrated in vacuo to afford 951 mg of thetitle amine (94%).

Amine 58

6-Benzyloxyindole-3-carboxaldehyde is converted to2-(6-benzyloxy-1H-indoyl-3-yl)-1,1-dimethylethylamine by sequentiallyfollowing the procedures detailed for Amine 61, 1^(st) paragraph, thenfor Amine 57, 1^(st) and 2^(nd) paragraphs.

A solution of 2-(6-benzyloxy-1H-indoyl-3-yl)-1,1-dimethylethylamine (4.9g, 16.6 mmol) in 125 ml of CH₂Cl₂ is treated with t-butyloxycarbonylanhydride (BOC₂O; 4.0 ml, 17.5 mmol). After stirring overnight atambient temperature, the reaction mixture is diluted with H₂O, and thelayers are separated. The organic layer is dried over Na₂SO₄ andconcentrated in vacuo. The crude residue is purified by flashchromatography (SiO₂; 20% ethyl acetate in hexanes) to give 5.01 g of[2-(6-benzyloxy-1H-indoyl-3-yl)-1,1-dimethylethyl]carbamic acidtert-butyl ester (76%).

A solution of [2-(6-benzyloxy-1H-indoyl-3-yl)-1,1-dimethylethyl]carbamicacid tert-butyl ester (4.62 g, 11.7 mmol) in 300 ml of ethanol istreated with 5% Pd/C (1.0 g), and the resulting mixture is shaken underan atmosphere of H₂ at 60 psi overnight at ambient temperature. Thereaction mixture is filtered over celite and concentrated in vacuo. Thecrude phenol is dissolved in 100 ml of dimethylformamide and treatedwith triton-B (8.5 ml, 17.6 mmol) and bromoacetonitrile (900microliters, 12.8 mmol). After 1.5 hours, the reaction mixture isdiluted with H₂O (100 ml), and the aqueous layer is extracted with ethylacetate (3×100 ml). The combined organic extracts are washed with H₂O(2×100 ml), dried over Na₂SO₄ and concentrated in vacuo. The cruderesidue is purified by flash chromatography (SiO₂; 20% ethyl acetate inhexanes) affording 954 mg of BOC protected amine 58 (24%).

The BOC protected amine is deprotected substantially as described forAmine 6 to give the title amine 58 in 66% yield.

Amine 59

The title amine is prepared from5-benzyloxy-3-(dimethylaminomethyl)-1H-indole by following theprocedures detailed for Amine 57, 1^(st) and 2^(nd) paragraphs, followedby the methods described for Amine 58, 2^(nd–4) ^(th) paragraphs.

Amine 60

Amine 60 is prepared from 7-fluoroindole by sequentially following themethods described for Amine 51, 1^(st) paragraph; Amine 49, 1^(st)paragraph; and Amine 51, 3^(rd) paragraph.

Amine 61

A solution of methyl 3-formylindole-6-carboxylate (8.0 g, 39.3 mmol) in270 ml methanol is treated with dimethylamine (40% aqueous; 267 ml, 2.56mol) at ambient temperature. After 45 minutes, NaBH₄ (4.45 g, 118.1mmol) is added, and the resulting mixture is heated at 55° C. for 3hours. The reaction mixture is allowed to cool then is diluted withCHCl₃ (200 ml) and brine (150 ml). The organic layer is washed withbrine, dried over Na₂SO₄ and concentrated in vacuo. The crude residue ispurified by flash chromatography (SiO₂; 100% ethyl acetate then 20% 2MNH₃/methanol in CHCl₃) to give 9.07 g of3-dimethylamino-methyl-1H-indole-6-carboxylic acid methyl ester (99%).Amine 61 is prepared from 3-dimethylaminomethyl-1H-indole-6-carboxylicacid methyl ester by essentially following the procedures detailed inAmine 49, 1^(st) paragraph; and Amine 51, 3^(rd) paragraph.

Amines 52, 56, 62, 65 and 87

The title amines are prepared from methyl indole-5-carboxylate,5-cyanoindole, methyl indole-7-carboxylate, 6-cyanoindole and4-cyanoindole, respectively, in a method similar to that described forthe preparation of Amine 51.

Amine 63

Amine 63 is prepared from Amine 62 in 61% yield by essentially followingthe procedure described for Amine 53.

Amine 64

The title amine is prepared as described for Amines 8a and 8b, 1^(st–6)^(th) paragraphs.

Amine 66

A solution of [2-(7-hydroxy-1H-indol-3-yl)-1,1-dimethyl-ethyl]-carbamicacid tert-butyl ester (609 mg, 2.0 mmol) is dissolved in drydimethylformamide (30 ml) under a nitrogen atmosphere and treated withsodium hydride (84 mg, 2.1 mmol, 60% dispersion in oil) addedportion-wise over a 10 minute period. The mixture is cooled in anice/water bath and methyl-2-chloroacetate (434 mg, 4.0 mmol) is addeddrop-wise over 20 minutes. The ice bath is removed and the mixturestirred at room temperature for 15 hours. The reaction is then quenchedwith saturated brine and extracted with ethyl acetate. The ethyl acetatelayer is dried and concentrated to give a crude residue, which ispurified by silica gel chromatography (gradient elution, chloroform with1%-10% of 20% methanol in acetonitrile) to give 230 mg of[2-(7-(methoxycarbomethoxy)-1H-indol-3-yl)-1,1-dimethyl-ethyl]-carbamicacid tert-butyl ester (30%).

A solution of methanesulfonamide (106 mg, 1.12 mmol) and trimethylaluminum (2.0 M in hexanes, 0.56 ml, 1.12 mmol) in dry dichloromethane(5.0 ml) is stirred at room temperature under a nitrogen atmosphere for20 minutes. A solution of[2-(7-(methoxycarbomethoxy)-1H-indol-3-yl)-1,1-dimethyl-ethyl]-carbamicacid tert-butyl ester (160 mg, 0.425 mmol) in dry dichloromethane (1.5ml) is added and the mixture is heated under reflux for 15 hours. Themixture is cooled to room temperature and quenched with 1 N HCl solution(3.4 ml) and partitioned between ethyl acetate and water. The organicextracts are dried over anhydrous Na₂SO₄, filtered and the solventevaporated to give 220 mg of[2-(7-(methanesulfonamidylcarbomethoxy)-1H-indol-3-yl)-1,1-dimethyl-ethyl]-carbamicacid tert-butyl ester (90%).

The title amine is prepared from[2-(7-(methanesulfonamidylcarbomethoxy)-1H-indol-3-yl)-1,1-dimethyl-ethyl]-carbamicacid tert-butyl ester as described for the preparation of Amine 1 (108mg, 70%).

Amine 67

[2-(7-Cyanomethoxy-1H-indol-3-yl)-1,1-dimethyl-ethyl]-carbamic acidtert-butyl ester (500 mg, 1.46 mmol) is dissolved in borane intetrahydrofuran (3.0 ml of a 1M solution, 3.0 mmol) under a nitrogenatmosphere and the resulting mixture is stirred at room temperature for18 hours. The mixture is then hydrolyzed by the addition of methanolsaturated with HCl gas (1.5 ml) followed by stirring at room temperaturefor 30 minutes. The solvent is evaporated and the residue treated withsaturated aqueous sodium bicarbonate (20 ml). The aqueous mixture isextracted with ethyl acetate (3×25 ml). The combined ethyl acetatelayers are dried and concentrated to give a crude residue, which ispurified by elution from SCX resin (20% of 2M NH₃ in methanol in CHCl₃)to give after evaporation 390 mg of[2-(7-(2-aminoethoxy)-1H-indol-3-yl)-1,1-dimethyl-ethyl]-carbamic acidtert-butyl ester (77%).

[2-(7-(2-Aminoethoxy)-1H-indol-3-yl)-1,1-dimethyl-ethyl]-carbamic acidtert-butyl ester (270 mg, 0.78 mmol) and 1H-benzotriazol-1-ylmethanesulfonate (Tet. Lett., 40:117–120, 1999; 170 mg, 0.82 mmol) indry dimethylformamide (6.0 ml) is stirred at room temperature under anitrogen atmosphere for 3 hours. The mixture is diluted with water (20ml) and extracted with ethyl acetate (2×20 ml). The combined organicextracts are washed with brine, dried over anhydrous Na₂SO₄, filteredand the solvent evaporated. The residue is taken up in 5% 2M NH₃ inmethanol in CHCl₃ (5 ml) and the solid removed by filtration.Evaporation of the filtrate gives 270 mg of2-(7-(2-methanesulfonylaminoethoxy)-1H-indol-3-yl)-1,1-dimethyl-ethyl]-carbamicacid tert-butyl ester (82%).

2-(7-(2-methanesulfonylaminoethoxy)-1H-indol-3-yl)-1,1-dimethyl-ethyl]-carbamicacid tert-butyl ester (350 mg, 0.82 mmol) is deprotected with 4.0M HClin dioxane to give 170 mg of the tiile compound (89%).

Amines 68–71

The title amines are prepared from trifluoro-methanesulfonic acid3-(2-tert-butoxycarbonylamino-2-methyl-propyl)-1H-indol-7-yl ester and:4-methoxycarbonylbenzeneboronic acid; 4-acetamidylbenzeneboronic acid;3-methoxycarbonylbenzeboronic acid; and5-methoxycaronylthiophen-2-ylboronic acid, respectively, using theprocedure described for the preparation of Amine 2.

Amine 72

The title amine is prepared from[1,1-dimethyl-2-(7-trifluoromethanesulfonylmethyl-1H-indol-3-yl)-ethyl]-carbamicacid tert-butyl ester and 1-vinylimidazole as described for thepreparation of Amine 23 (36%) FDMS m/e=282.2 (M⁺+1).

Amine 73

(2-{7-[2-(4-Cyano-phenyl)-vinyl]-1H-indol-3-yl}-1,1-dimethyl-ethyl)-carbamicacid tert-butyl ester is prepared from[1,1-dimethyl-2-(7-trifluoromethanesulfonylmethyl-1H-indol-3-yl)-ethyl]-carbamicacid tert-butyl ester and 4-cyanostyrene as described for thepreparation of Amine 23 (93%). FDMS m/e=315.2 (M⁺+1).

The title amine is prepared from(2-{7-[2-(4-cyano-phenyl)-vinyl]-1H-indol-3-yl}-1,1-dimethyl-ethyl)-carbamicacid tert-butyl ester as described for the preparation of Amine 28. FDMSm/e=318.2 (M⁺+1).

Amine 74

{1,1-Dimethyl-2-[7-(2-pyrazin-2-yl-vinyl)-1H-indol-3-yl]-ethyl}-carbamicacid tert-butyl ester is prepared from[1,1-dimethyl-2-(7-trifluoromethanesulfonylmethyl-1H-indol-3-yl)-ethyl]-carbamicacid tert-butyl ester and 2-vinylpyrazine as described for thepreparation of Amine 23 (99%). FDMS m/e=393.2 (M⁺+1)

The Boc-protecting group on{1,1-dimethyl-2-[7-(2-pyrazin-2-yl-vinyl)-1H-indol-3-yl]-ethyl}-carbamicacid tert-butyl ester is removed as described in Amine 6 to give thetitle amine (94%) FDMS m/e=293.2 (M⁺+1).

Amine 75

The title amine is prepared from[1,1-dimethyl-2-(7-trifluoromethanesulfonylmethyl-1H-indol-3-yl)-ethyl]-carbamicacid tert-butyl ester and p-sulfonamido styrene as described for thepreparation of Amine 23 (70%). FDMS m/e=370.2 (M⁺+1).

Amine 76

Trifluoro-methanesulfonic acid3-(2-tert-butoxycarbonylamino-2-methyl-propyl)-1H-indol-6-yl ester isprepared from 6-benzyloxy gramine and 2-nitropropane as described in thepreparation of Amine 1, 1^(st–5) ^(th) paragraphs.Trifluoromethanesulfonic acid3-(2-tert-butoxycarbonylamino-2-methyl-propyl)-1H-indol-6-yl ester andacrylonitrile are reacted and the Boc-protecting group is removed fromthe resulting product as described in the prepararation of Amine 23 togive the title amine (75%). FDMS m/e=240.2 (M⁺+1).

Amine 77

The 7-nitroindole (20.0 g, 123.3 mmol) and Eschenmoser's salt (24.0 g,129.5 mmol) are suspended in glacial acetic acid (500 mL) and stirred at65° C. for 1 hour. The reaction mixture is cooled and the resultingsolid filtered, and washed with ethyl acetate (2×50 mL). This solid isthen dried in a vacuum oven overnight to yield 39.3 g of the desired7-nitrogramine hydroiodide salt (89.4%).

The 7-nitrogramine salt (2.0 g, 5.8 mmol) is suspended in a mixture of2-nitropropane (9.5 mL) and methanol (9.5 mL). Dimethylsulfate (1.09 mL,11.5 mmol) is added dropwise via syringe, and the resulting yellowsolution is stirred at room temperature for 5 minutes. Sodium methoxide(0.62 g, 11.5 mmol) is then added in one portion, and the mixture isstirred overnight at room temperature. The reaction is quenched byaddition of saturated NH₄Cl solution and ethyl acetate. The aqueouslayer is extracted with ethyl acetate, and the combined organic layersare washed with brine, and dried over Na₂SO₄ to give 1.0 g of3-(2-nitro-2-methylpropyl)-7-nitroindole (69%).

3-(2-Nitro-2-methylpropyl)-7-nitroindole (1.89 g, 7.2 mmol) is dissolvedin ethyl acetate (75 mL) and 10% Pd/C is added (750 mg). The mixture isstirred under a balloon of nitrogen for 2–3 hours. The mixture isfiltered to remove the Pd/C, and the filtrate is evaporated to give acrude oil. This crude 3-(2-nitro-2-methylpropyl)-7-aminoindole isimmediately dissolved in pyridine (100 mL) and the solution is cooledwith an ice bath to 0° C. Benzenesulfonyl chloride is added slowly, andthe mixture is stirred for 5 minutes at this temperature before removingthe ice bath. The reaction mixture is stirred overnight before beingquenched by addition of 1N HCl and ethyl acetate. The aqueous layer isextracted with ethyl acetate several times and the combined organicextracts are washed twice with brine and dried over Na₂SO₄ to give acrude oil. The crude material is purified by flash chromatography (25%ethyl acetate/hexanes) to provide 1.9 g of3-(2-nitro-2-methylpropyl)-7-benzenesulfonamidyl-indole (71%).

3-(2-Nitro-2-methylpropyl)-7-benzenesulfonamidyl-indole (1.90 g, 5.1mmol) is charged to a Parr reaction vessel and is dissolved in3A-ethanol (500 mL). Raney Nickel (5 g) is added to the solution. Thereaction is pressurized with hydrogen and is hydrogenated overnight at60° C. under a hydrogen pressure of 60 psi. When the reaction iscomplete, the reaction mixture is cooled to ambient temperature and theRaney Nickel is removed by vacuum filtration. The solvent is evaporatedto give the title amine.

Amine 78

3-(2-Nitro-2-methylpropyl)-7-methanesulfonamidyl-indole is prepared fromcrude 3-(2-nitro-2-methylpropyl)-7-aminoindole and methanesulfonylchloride and 3-(2-nitro-2-methylpropyl)-7-methanesulfonamidyl-indole isconverted to the title amine by the procedure described for Amine 77(2.3 g).

Amine 79

The Boc-protected title amine is prepared from Boc-α-methylalanine andindoline by the procedure described above for Amine 20 except that thereaction is conducted in dichloromethane and the crude Boc-protectedamine is purified by normal phase flash chromatography (silica gel,20–60% ethyl acetate/hexanes).

To a mixture of the Boc-protected title amine (1.0 g, 3.3 mmol) indioxane (8 mL) at room temperature is added 4M HCl/dioxane (8 mL). Thereaction mixture is stirred overnight at room temperature, and thenconcentrated. The resulting material is dissolved in methanol (10 mL),purified using a cation exchange column, and concentrated to give 640 mgof the title amine (95%).

Amine 80

To a solution of{1,1-dimethyl-2-[7-(2-[1,2,4]triazol-1-yl-vinyl)-1H-indol-3-yl]-ethyl}-carbamicacid tert-butyl ester (1.0 g, 2.55 mmol) in methanol (20.0 mL), is added10% Pd/C (0.50 g) in methanol (2.0 mL). The reaction mixture is purgedwith hydrogen and hydrogenation is carried out with a hydrogen balloonovernight. The reaction mixture is filtered, and the filtrate isevaporated to dryness to give 850 mg of{2-[7-(2-methanesulfonyl-ethyl)-1H-indol-3-yl]-1,1-dimethyl-ethyl}-carbamicacid tert-butyl ester (81%). FDMS m/e=395.2 (M⁺+1).

To solution of{1,1-Dimethyl-2-[7-(2-[1,2,4]triazol-1-yl-ethyl)-1H-indol-3-yl]-ethyl}-carbamicacid tert-butyl ester (220 mg, 0.57 mmol) in dioxane (5.0 mL) at roomtemperature is added 4N HCl (5.0 mL). The reaction mixture is stirred atroom temperature for 1 hour. The reaction mixture is evaporated todryness, residue is taken up with water (25.0 mL), saturated NaHCO₃ (5.0mL) is added, and the mixture is extracted with ethyl acetate (2×50 mL).The organic extracts are washed with brine, dried (Na₂SO₄) andevaporated to dryness to give 150 mg of the title amine (90%).

Amine 81

3-Trifluoromethyl-bromobenzene (1 equivalent) is dissolved indimethylsulfoxide (3 ml/mmol) under argon and bis-(pinacolato)-diboron(1.1 equivalents), potassium acetate (3 equivalents) and1,1′-bis(diphenylphosphino)ferrocene)palladium(II)dichloride-dichlormethanecomplex (0.03 equivalents) are added. The resulting mixture is heated to80° C. and then stirred for two hours at this temperature. The mixtureis cooled to room temperature, and trifluoro-methansulfonic acid3-(2-tert-butoxycarbonylamino-2-methyl-propyl)-1H-indol-7-yl ester (0.8equivalents), 1,1′-bis(diphenylphosphino)ferrocene)palladium(II)dichloride-dichlormethane (0.03 equivalents) and2M Na₂CO₃ (5 equivalents) are added under argon. The resulting mixtureis heated to 80° C. and then allowed to stir overnight at thistemperature. The mixture is diluted with water and extracted with ethylacetate or CH₂Cl₂. The organic extract is washed once with brine, thendried over Na₂SO₄, filtered and evaporated. The residue ischromatographed (silica gel, CH₂Cl₂/ethanolic NH₃, 98/2) to give theBoc-protected title compound.

The Boc-protected amine is dissolved in 5N HCl in isopropanol (5ml/mmol) and stirred overnight at room temperature. The mixture isevaporated, dissolved in ethanol and loaded onto a 5 g SCX columnconditioned with methanol. The column is washed twice with 5 ml ethanolto remove impurities. The title compound is then eluted with 5 mlethanolic NH₃ and 5 ml ethanol. Evaporation of the solvent gives thedeprotected amine.

Amines 82–84

The title amines are prepared from trifluoro-methansulfonic acid3-(2-tert-butoxycarbonylamino-2-methyl-propyl)-1H-indol-7-yl ester and:ethyl 3-bromobenzoate; 3′-bromoacetophenone; and 4′-bromoacetophenone,respectively, using the procedure described for the preparation of Amine81.

Amine 85

Amine 85 is prepared by hydrolysis of the methyl ester of Amine 62 byessentially following the procedure detailed for Amine 86.

Amine 86

A solution Amine 61 (2 g, 8.12 mmol) in 24 ml of tetrahydrofuran and 8ml of MeOH is treated with 1M aqueous LiOH (8.1 ml). The resultingmixture is heated overnight at 60° C. An additional portion of 1Maqueous LiOH (2 ml) is added and heating is continued for 24 hours todrive the hydrolysis to completion. The reaction mixture is concentratedin vacuo to give the crude lithium salt as a white solid.

Amine 88

Amine 88 is prepared from indole-2-carboxylic acid and1,2-diamino-2-methylpropane by essentially following the proceduredetailed for Amine 55.

Boronic Acids

Boronic Acids 1–5 are obtained from commercial sources for use asdescribed in Scheme 2. These boronic acids are pictured below in Table3.

TABLE 3

1

2

3

4

5Aryl Halides of Formula V

A solution of Epoxide 22 (496 mg, 1.69 mmol) and Amine 6 (410 mg, 1.69mmol) in dry ethanol (10 ml) is heated at 110° C. overnight. Afterevaporation of the solvent, the residue is purified via flashchromatography (silica gel, dichloromethane/ethanol 95:5 to 85:15) togive 150 mg of the title compound (17%). MS m/e=538.2 (M⁺+1).

The title compound is prepared from Epoxide 31 and Amine 6 as describedabove for Aryl Halide 1.

The title compound is prepared from Epoxide 31 and Amine 11 as describedabove for Aryl Halide 1.

Representative Procedure 1: Amination of Epoxide

A vial is charged with a solution of single amine of formula III (0.2Min ethanol or t-butanol, 90 micromolar) and a solution of a singleepoxide of formula II (0.2M in dimethylsulfoxide, 80 micromolar). Thevial is sealed and heated to 80° C. for 24–48 hours. The solution iscooled to room temperature, diluted with methanol, and passed over acation exchange column, eluting the basic material with 1N methanolicammonia.

Representative Procedure 2: Amination of Epoxide

A stirred mixture of an epoxide of formula II (1 equivalent) and anamine of formula II (1–2 equivalents) in ethanol, methanol, n-butanol ort-butanol is heated at 70–80° C. for 2–72 hours. The solvent isevaporated to dryness to give a crude oil that is optionally dilutedwith methanol or ethanol and passed over a cation exchange column(eluting the free base product with 1N methanolic ammonia) beforefurther purification.

The final products prepared via Representative Procedure 1 or 2 may befurther purified by flash or radial chromatography. Typicalchromatography conditions include: a) using a variable mixture of 25:5:1chloroform/methanol/ammonium hydroxide and 9:1 chloroform/methanol; b) avariable mixture of 90:10:1 CH₂Cl₂/ethanolic NH₃ gradient; c)dichloromethane/6–12% methanol, 0.15–0.35M ammonia in dichloromethanegradient; d) methylene chloride with a step gradient to 2–8% methanol;e) chloroform/2.0M ammonia in methanol, from 0–10% to 6–20% gradientelution or f) isocratic 6–8% 2M ammonia in methanol: 92–94%dichloromethane.

Alternatively, the final products may be purified on C18 bonded silicagel using either mass guided or UV guided reverse phase liquidchromatography (acetonitrile/water with 0.01% hydrochloric acid or 0.1%trifluoroacetic acid). When purification of a compound of the presentinvention results in production of a free base, the free base thusprepared may be salified, e.g., by dissolution of the free base inCH₂Cl₂ or diethylether, adding 1M ethanolic HCl or a solution of HCl indiethylether, and evaporating the volatiles, or as described in moredetail below.

For example, a hydrochloride salt may be prepared by dissolving the freebase in dichloromethane, diethylether, or a mixture of ethyl acetate andmethanol and adding 1M ethanolic HCl, a solution of HCl in diethylether,or 0.5M ammonium chloride. The resultng mixture is allowed to stir for ashort time, e.g., for five minutes, before evaporating the volatiles andoptionally triturating in diethyl ether to give the hydrochloride salt.

The oxalate salts may be prepared by dissolving the free base in a smallamount of ethyl acetate, optionally adding methanol for solubitity. Theresulting solution is treated with 1 equivalent of a 0.5M solution ofoxalic acid in ethyl acetate. The reaction mixture is eitherconcentrated in vacuo or centrifuged, separated, and the solids aredried, to give the oxalate salt.

To prepare a succinate salt, the free base may be dissolved in a smallamount of ethyl acetate or methanol and then treated with 1 equivalentof succinic acid in methanol. The resulting slurry is dissolved in theminimum amount of methanol then concentrated in vacuo to give thesuccinate salt.

The table below sets out representative combinations of Amines andEpoxides that are reacted as described in Representative Procedure 1 or2. Preparation of desired product is confirmed via mass spectralanalysis (MSA). Emax±Standard Error Mean (SEM) data, discussed in the“Demonstration of Function” section below, is also included for saidcompounds where available. The Emax values represent the average of atleast 3 runs except as otherwise indicated.

TABLE 4 Isolated Emax (%) ± E.g. Epoxide Amine MSA Form SEM 1 3 6 459.2Free Base 64.1 ± 4.5 2 3 8 445.4 Free Base 44.5 ± 4.6 3 3 9 477.2 FreeBase 68.9 ± 2.6 4 3 10 463.3 Free Base 52.3 ± 1.7 5 10 6 460.2Hydrochloride 66.0 ± 3.6 6 11 6 461.5 Trifluoro Acetate 55.0 ± 3.4 7 9 6461.3 Trifluoro Acetate 58.4 ± 1.7 8 8 6 461.3 Trifluoro Acetate 82.2 ±3.8 9 8 8 447.5 Trifluoro Acetate 49.5 ± 3.3 10 14 6 475.0 TrifluoroAcetate 63.2 ± 5.3 11 15 11 446.0 Hydrochloride 69.0 ± 2.3 12 15 6 501.3Trifluoro Acetate 77.7 ± 4.6 13 16 11 435.3 Trifluoro Acetate 63.4 ± 0.314 16 6 490.2 Trifluoro Acetate 75.2 ± 3.0 15 17 11 446.3 TrifluoroAcetate 50.2 ± 7.3 16 17 6 501.5 Trifluoro Acetate 54.2 ± 2.2 17 18 11435.2 Trifluoro Acetate 43.1 ± 3.0 18 18 6 490.1 Trifluoro Acetate 52.3± 0.7 19 19 11 446.2 Trifluoro Acetate 49.1 ± 4.6 20 19 6 501.3Trifluoro Acetate 59.1 ± 3.1 21 20 11 435.1 Trifluoro Acetate 61.3 ± 3.222 20 6 490.3 Trifluoro Acetate 66.0 ± 0.9 23 5 6 461.2 HydrochlorideNot Tested 24 2 6 477.2 Hydrochloride Not Tested 25 1 77 576.1 Free Base 89.6 ± 10.9 26 4 77 561.2 Hydrochloride 70.9 ± 5.4 27 1 78 514.1Hydrochloride 81.0 ± 3.2 28 4 78 499.1 Hydrochloride 58.5 ± 0.5 29 28 78514.2 Hydrochloride 68.5 ± 1.3 30 29 78 593.2 Hydrochloride 90.0 ± 6.631 11 11 406.2 Hydrochloride 62.4 ± 2.1 32 3 11 404.2 Free Base 58.9 ±1.9 33 8 11 406.0 Free Base 75.9 ± 1.9 34 9 11 406.2 Free Base 64.5 ±2.1 35 27 11 429.2 Free Base 50.3 ± 2.2 36 14 11 420.2 Free Base 63.9 ±1.6 37 1 81 565.2 Hydrochloride 82.0 ± 4.3 38 4 81 550.4 Hydrochloride78.0 ± 2.8 39 3 81 548.4 Hydrochloride 71.7 ± 3.0 40 1 82 569.2Hydrochloride 73.3 ± 4.6 41 4 82 554.4 Hydrochloride 73.1 ± 1.0 42 3 82552.2 Hydrochloride 61.0 ± 4.5 43 1 68 555.2 Hydrochloride 66.6 ± 3.1 444 68 540.2 Hydrochloride 38.5 ± 2.3 45 3 68 538.4 Hydrochloride 41.9 ±4.5 46 1 83 539.4 Hydrochloride 68.2 ± 2.2 47 4 83 524.4 Hydrochloride69.2 ± 2.0 48 1 84 539.2 Hydrochloride 60.4 ± 6.0 49 4 84 524.4Hydrochloride 44.2 ± 1.2 50 3 84 522.6 Hydrochloride 38.4 ± 3.2 51 30 11457.0 Hydrochloride 58.3 ± 1.3 52 30 6 512.1 Hydrochloride 74.0 ± 3.1 5329 78 593.2 Hydrochloride 90.0 ± 6.6 54 29 85 544.1 Trifluoroacetate79.0 ± 3.5 55 29 86 544.1 Trifluoroacetate 78.4 ± 0.2 56 1 78 514.1Hydrochloride 81.0 ± 3.2 57 4 78 499.1 Hydrochloride 58.5 ± 0.5 58 28 78514.2 Hydrochloride 68.5 ± 1.3 59 28 6 476.4 Trifluoroacetate 70.4 ± 4.060 28 11 421.3 Trifluoroacetate 86.5 ± 5.9 61 30 85 465.2 Hydrochloride56.6 ± 2.7 62 30 86 465.2 Hydrochloride 63.8 ± 0.5 63 1 44 517.2 Oxalate55.7 ± 0.8 64 1 46 393.2 Hydrochloride 22.2 ± 4.5 65 1 47 393.2Hydrochloride 34.5 ± 7.3 66 2 44 408.2 Hydrochloride 34.8 ± 3.2 67 1 48462.2 Hydrochloride 28.6 ± 3.4 68 2 11 422.2 Hydrochloride 53.2 ± 1.6 691 51 479.2 Hydrochloride 39.1 ± 7.1 70 1 52 479.2 Hydrochloride 37.3 ±2.7 71 1 53 464.1 Hydrochloride 47.4 ± 1.8 72 1 54 421.2 Hydrochloride48.0 ± 2.1 73 1 55 464.1 Hydrochloride 32.1 ± 3.3 74 1 56 446.2Hydrochloride 28.3 ± 2.6 75 1 61 479.2 Hydrochloride 47.2 ± 0.3 76 1 62479.2 Hydrochloride 67.6 ± 5.2 77 1 65 446.2 Hydrochloride 73.9 ± 1.3 784 65 431.2 Hydrochloride 58.6 ± 0.9 79 23 11 422.0 Hydrochloride 58.2 ±2.3 80 24 11 424.2 Hydrochloride 43.4 ± 2.0 81 25 11 424.2 Hydrochloride35.1 ± 2.1 82 7 11 423.2 Hydrochloride 45.5 ± 3.5 83 6 11 422.2Hydrochloride 73.7 ± 2.0 84 26 11 423.2 Hydrochloride 34.3 ± 2.8 85 1 18422.0 Hydrochloride 66.8 ± 3.2 86 4 18 407.0 Hydrochloride 52.5 ± 3.1 8716 85 479.2 Hydrochloride 76.5 ± 2.7 88 20 85 479.2 Hydrochloride 71.0 ±6.5 89 18 85 479.2 Hydrochloride 49.1 ± 1.9 90 15 85 490.2 Hydrochloride90.4 ± 3.8 91 19 85 490.2 Hydrochloride 54.7 ± 2.8 92 17 85 490.2Hydrochloride 60.2 ± 1.8 93 16 86 479.2 Hydrochloride 73.9 ± 2.0 94 2086 479.2 Hydrochloride 64.0 ± 2.6 95 18 86 479.2 Hydrochloride 51.5 ±3.3 96 15 86 490.2 Hydrochloride 74.1 ± 2.4 97 19 86 490.2 Hydrochloride71.3 ± 0.8 98 17 86 490.2 Hydrochloride 57.7 ± 0.3 99 1 87 446.2Hydrochloride 62.6 ± 4.7 100 1 88 NC Hydrochloride <10 101 1 6 476.0Succinate  76.5 ± 12.6 102 1 1 540.0 Succinate 69.0 ± 2.2 103 4 1 525.0Succinate 57.1 ± 2.4 104 1 2 565.0 Succinate 59.2 ± 1.0 105 4 2 550.0Succinate 69.1 ± 3.8 106 1 3 503.0 Succinate 78.0 ± 8.5 107 4 3 488.0Succinate 57.9 ± 6.2 108 1 4 503.0 Succinate 71.5 ± 7.9 109 4 4 488.0Succinate 68.0 ± 4.1 110 1 5 633.0 Succinate 72.7 ± 5.3 111 4 5 618.0Succinate 86.0 ± 4.0 112 1 12 539.0 Succinate 97.7 ± 5.9 113 4 12 524.0Succinate 76.5 ± 3.0 114 1 13 539.0 Succinate 72.1 ± 5.0 115 1 14 539.0Succinate 83.3 ± 4.0 116 4 14 524.0 Succinate 58.1 ± 1.6 117 1 15 572.0Succinate 67.6 ± 3.9 118 1 16 471.9 Oxalate 40.3 ± 2.9 119 4 16 457.9Oxalate 35.2 ± 3.5 120 1 17 438.2 Oxalate 68.0 ± 4.9 121 13 17 438.9Oxalate 39.1 ± 1.3 122 12 17 455.9 Oxalate 66.1 ± 2.9 123 21 17 495.9Oxalate 44.4 ± 5.2 124 21 11 479.0 Oxalate 36.1 ± 7.6 125 13 11 422.2Oxalate 59.2 ± 2.2 126 12 11 439.0 Oxalate 76.1 ± 2.9 127 4 17 423.2Oxalate 50.1 ± 7.4 128 1 19 409.1 Hydrochloride 46.5 ± 3.0 129 4 19394.3 Hydrochloride 35.2 ± 3.3 130 1 20 423.2 Hydrochloride 36.3 ± 1.8131 1 21 423.2 Hydrochloride 23.6 ± 1.7 132 4 6 461.2 Free Base 53.6 ±1.4 133 4 6 461.0 Succinate 60.6 ± 2.4 134 4 8 447.1 Free Base 59.6 ±4.4 135 4 8 447.1 Free Base 30.0 ± 3.9 136 4 22 495.0 Free Base 47.9 ±3.6 137 1 6 476.2 Free Base 65.5 ± 4.7 138 1 8 462.1 Free Base 54.8 ±8.0 139 1 25 490.2 Succinate 86.5 ± 5.5 140 1 26 492.2 Succinate 83.5 ±2.7 141 1 27 525.1 Succinate 65.0 ± 2.0 142 1 28 527.2 Succinate 82.1 ±1.4 143 1 29 472.1 Succinate 66.4 ± 8.7 144 1 30 474.1 Succinate 73.3 ±5.9 145 1 24 507.1 Succinate 79.3 ± 7.1 146 1 31 514.1 Succinate 47.3 ±2.3 147 1 23 505.2 Free Base Not Tested 148 4 32 446.3 Free Base 18.9 ±1.5 149 1 32 461.3 Free Base <10 150 4 39 447.1 Oxalate 46.6 ± 1.9 151 639 463.0 Oxalate 52.4 ± 4.3 152 1 39 462.3 Oxalate 63.1 ± 4.4 153 1 40465.2 Oxalate 45.2 ± 8.4 154 1 41 465.2 Oxalate 32.4 ± 8.1 155 1 42462.2 Oxalate  58.7 ± 13.4 156 1 43 476.2 Oxalate 41.9 ± 9.3 157 1 11421.2 Oxalate 51.3 ± 7.8 158 1 57 439.2 Oxalate 69.6 ± 4.8 159 2 57440.2 Oxalate 53.0 ± 1.8 160 7 6 478.2 Oxalate 44.3 ± 3.9 161 7 8b 464.2Oxalate 21.7 ± 3.1 162 1 49 439.2 Hydrochloride 64.2 ± 7.6 163 1 50439.2 Hydrochloride 57.1 ± 5.8 164 4 11 406.2 Hydrochloride 53.9 ± 2.6165 4 44 392.2 Hydrochloride 37.1 ± 4.0 166 4 49 424.2 Hydrochloride47.8 ± 0.6 167 4 50 424.2 Hydrochloride 40.8 ± 1.3 168 1 58 476.2Hydrochloride 62.1 ± 3.3 169 1 59 476.2 Hydrochloride 51.9 ± 3.4 170 160 439.2 Hydrochloride 71.2 ± 1.2 171 2 60 440.2 Hydrochloride 56.0 ±1.5 172 4 57 424.2 Hydrochloride 55.0 ± 1.1 173 4 60 424.2 Hydrochloride50.2 ± 1.5 174 1 63 463.6 Hydrochloride 57.6 ± 0.6 175 4 63 448.5Hydrochloride 41.1 ± 3.5 176 1 66 572.0 Trifluoroacetate 79.0 ± 2.9 1771 67 558.0 Free Base 73.8 ± 1.5 178 1 68 555.0 Succinate 72.5 ± 2.2 1791 69 554.0 Succinate 71.5 ± 1.1 180 1 70 555.0 Succinate Not Tested 1811 71 561.0 Free Base Not Tested 181 4 68 540.0 Succinate 39.6 ± 0.7 1834 69 539.0 Succinate 47.7 ± 1.6 184 4 70 540.0 Succinate Not Tested 1851 24 507.2 Succinate 79.3 ± 7.1 186 1 72 513.0 Succinate 66.5 ± 0.4 1871 73 550.2 Succinate 77.9 ± 0.7 188 1 74 525.1 Succinate 70.5 ± 3.8 1891 75 602.3 Succinate 64.5 ± 1.7 190 1 76 472.2 Succinate 69.3 ± 1.3 19129 11 500.1 Hydrochloride 85.6 ± 7.8 192 1 79 437.2 Hydrochloride 55.6 ±6.0 193 4 79 422.2 Hydrochloride 32.0 ± 5.5

ALTERNATE PREPARATION OF EXAMPLE 1

Amine 6 (12.08 g, 43.2 mmol, 1.10 equivalents) is dissolved inacetonitrile (86 mL) containing N-(trimethylsilyl)acetamide (95% pure,5.1 g, 39.2 mmol, 1.0 equivalent—warmed to effect dissolution). Epoxide3 is then added (8.0 g, 96% pure, 1.0 equivalent) and the solution isallowed to stand at 24–26° C. for 45 hours after which water (10 mL) andacetic acid (6.3 g) are added. After 1.5 hours, the bulk of the solventsare removed under vacuum (25° C., 10 mm, 16 hours). The resulting glassis partitioned between ethyl acetate (250 mL) and 1 N NaOH (300 mL). Theaqueous layer is washed with ethyl acetate (100 mL). The organic layersare combined and washed with water (2×100 mL), saturated brine solution(100 mL), dried (20 g molecular sieves) and evaporated under vacuum. Theresidue is chromatographed (linear gradient of 0% to 35% methanol inethyl acetate) to afford, after evaporation of the solvent, 14.4 g ofthe title compound (87%). IR (CHCl₃): 3478 cm⁻¹; UV (ethanol): λ(ε)279(9000), 246 (10,970), 219 (55370); ES MS: 458.2396.

Example 194

A stirred mixture of Epoxide 1 (1 equivalent), Amine 34 (1.0–1.2 eq) andytterbium trifluoromethane sulfonate hydrate (0.1 equivalent) in 10 mlCH₃CN is heated at 80° C. for 20–60 hours. Upon completion, the reactionis diluted with ethyl acetate, washed with brine, dried (Na₂SO₄), andthe solvent is evaporated to dryness. The ethanolamine product ispurified by flash chromatography using a variable mixture of 90:10:1CH₂Cl₂/methanol/NH₄OH. MS(ES+) 443.1. Emax (SEM)=25.6 (1.8).

Example 195

Epoxide 1 (232 mg, 1 mmol), Amine 33 (255 mg, 1.1 mmol), and ytterbiumtrifluoromethane sulfonate hydrate (62 mg, 0.1 mmol) in 10 mlacetonitrile are reacted and purified as in Example 194 to give 92 mg ofthe free base of the title compound (20%). A 5 ml methanol solution ofthe free base (92 mg, 0.2 mmol) and NH₄Cl (11 mg, 0.2 mmol) is stirredfor 5 minutes at room temperature, concentrated, triturated indiethylether, filtered, and dried to give 95 mg of the title compound.MS(ES+) 459.1 (free base). Emax (SEM)=8.9 (1.7).

The table below sets out representative combinations of Amines andEpoxides that are reacted as described above in Example 194.

TABLE 5 Isolated Emax (%) ± E.g. Epoxide Amine MSA Form SEM 196 1 36443.1 Free Base 15.8 ± 2.6 197 1 37 457.2 Free Base 34.5 ± 4.2 198 1 38455.2 Free Base 12.5 ± 1.1

Example 199

A solution of Amine 64 (105 mg, 0.457 mmol) and Epoxide 5 (82.6 mg,0.381 mmol) in 2 ml of acetonitrile is treated with ytterbiumtrifluoromethane sulfonate hydrate (23.6 mg, 0.038 mmol). The resultingmixture is heated at 60° C. over 3 days and then quenched with H₂O andextracted with ethyl acetate (3×50 ml). The combined organic extractsare dried over Na₂SO₄ and concentrated in vacuo. The crude residue ispurified by radial chromatography (SiO₂; 3% 2M NH₃/methanol in CHCl₃) togive 51 mg (30%) of the free base. The free base is dissolved in a smallamount of ethyl acetate, optionally adding methanol for solubitity. Theresulting solution is treated with 1 equivalent of a 0.5M solution ofoxalic acid in ethyl acetate. The reaction mixture is eitherconcentrated in vacuo or centrifuged, separated, and the solids aredried, to give the title compound. MS 448.1. Emax (SEM)=22.8 (n=1).

Examples 200 & 201

Racemic Amine 45 and Epoxide 1 are coupled in a fashion similar to thatdescribed in Representative Procedure 2 to give a mixture of the freebases of the title compounds. The title compounds are separated, onefrom the other, by normal phase chiral HPLC (Chiralpak AD; 15% 3Aethanol in heptane with 0.2% dimethylethylamine) to give the free baseof Example 200 (faster eluting) in 40% yield and the free base ofExample 201 in 35% yield. The oxalate salts are prepared by separatelydissolving each of the free base isomers in a small amount of ethylacetate, optionally adding methanol for solubility. The resultingsolution is treated with 1 equivalent of a 0.5M solution of oxalic acidin ethyl acetate. The reaction mixture is either concentrated in vacuoor centrifuged, separated, and the solids are dried, to give the oxalatesalts. Emax (SEM)=28.8 (4.4) and 36.3 (9.8), respectively.

Example 202

To a solution of Amine 6 (11.9 g, 48.8 mmol) dissolved in ethanol (120mL) is added a solution of Epoxide 15 (12.0 g, 43.6 mmol) dissolved inethanol (30 mL). The solution is heated to reflux and the solution isstirred at the reflux temperature for 19 hours. The solvent is removedin vacuo and the solid is purified by Biotage chromatography (97.9:2:0.1dichloromethane:methanol:concentrated ammonia hydroxide gradient to95.9:4:0.1 dichloromethane:methanol:concentrated ammonia hydroxide as aneluent) to give 9.6 g of a solid. The solid is dissolved in 1,4 dioxane(100 mL) and 4 M HCl in dioxane (4.8 mL, 19.2 mmol) is added. Thesolution is stirred for 5 minutes and the solid is collected by vacuumfiltration. The solid is dissolved in dichloromethane (100 mL) andcooled to 0° C. in ice. The precipitate is collected by vacuumfiltration and the filter cake is slurried in ethyl acetate (100 mL) andheated at a reflux for 1 hour. The mixture is filtered to give 9.44 g ofthe title compound (39%). FDMS m/e=501.2 (M⁺+1). Emax (SEM)=85.0 (3.5).

Example 203

Epoxide 3 is reacted with Amine 7 according to the RepresentativeProcedure 2. The crude amination mixture (290 mg) is dissolved in 10 mlethanol, 2M NaOH (2 ml) is added and the resulting mixture is left tostir at room temperature overnight. The solution is neutralized withacetic acid and loaded on a SCX column. After washing with ethanol, theproduct is eluted with 10% NH₃ in ethanol. The fractions containingproduct are combined and evaporated to yield 220 mg of the titlecompound (80%). MS (positive ion): 478.4. Emax (SEM)=73.8 (8.0).

Example 204

A solution of Amine 61 (1.2 equiv) and Epoxide 2 in t-butanol (0.2 M) isheated at 80° C. for 24 hours. The solution of the crude free base istreated directly with crushed solid NaOH (5 equivalents). The resultingmixture is heated for 3 days at 70° C. then concentrated. Purificationof the crude product by reverse phase HPLC (YMC ODSA C18 5 micrometercolumn, gradient of 5–95% CH₃CN in H₂O with 0.01% HCl, 20 ml/minute,over 12 minutes) affords the title compound. MS 466.0. Emax (SEM)=67.0(2.6).

The table below sets out representative combinations of Amines andEpoxides that are reacted as described above in Example 204.

TABLE 6 Isolated Emax (%) ± E.g. Epoxide Amine MSA Form SEM 205 23 61466.0 Hydrochloride 51.1 ± 3.8 206 5 62 450.0 Hydrochloride 42.0 ± 4.3207 23 62 466.0 Hydrochloride 48.2 ± 3.3 208 13 62 466.0 Hydrochloride58.2 ± 3.1 209 4 62 450.0 Hydrochloride 58.0 ± 2.6Representative Procedure 5: Suzuki CouplingProcedure 5(a)

A compound of formula V (6.4 mmol) is dissolved in 50 ml of dry dioxaneand thoroughly flushed with argon. Palladium(0)tetrakis(triphenylphosphine) (750 mg, 0.64 mmol) is added under argonand stirred at ambient temperature until the mixture becomes homogenous.The clear solution is divided into aliquots of 2 ml, and each testingtube is charged with 2 equivalents of an aryl boronic acid and 500microliters of 2M aqueous sodium carbonate under argon. The testingtubes are sealed and heated in a microwave oven (MLS ETHOS 1600) for 35minutes and 100° C. at 1000 W. After complete conversion the samples arediluted with 2 ml of water and extracted with 3 ml of dichloromethane.Extraction is repeated with 2 ml of dichloromethane. The organicsolutions are collected and dried over sodium sulfate. The organicfiltrate is treated with pre-treated Amberlyst 15 (3 to 4 g each).(Prior to use Amberlyst 15 is prewashed with dichloromethane, ethanolthen dichloromethane until the filtrate is colorless). The suspensionsare shaken for 30 minutes on an orbital shaker and filtered. TheAmberlyst is repeatedly rinsed with dichloromethane/ethanol 1:1 (4×3 ml)and then repeatedly treated with dichloromethane/ethanolic ammonia 1:1.Finally the resin is treated with ethanolic ammonia overnight. Thealkaline filtrates are collected and evaporated.

Procedure 5(b)

A mixture of an aryl halide of formula V (1.2 mmol), a boronic acid (2.4mmol), palladium(0) tetrakis(triphenylphosphine) (0.06 mmol), and 2Maqueous sodium carbonate (1.5 ml) in dioxane (20 ml) is heated overnightat 100° C. in a sealed tube. The mixture is poured into water andextracted two times with ethyl acetate. The combined organic layers arewashed with brine, dried over sodium sulfate, and concentrated underreduced pressure.

The final products prepared via Suzuki coupling may be purified bynormal phase chromatography (silica gel, dichloromethane/ethanolicammonia) providing the free bases or by reverse phase chromatography(acetonitrile/0.1% trifluoroacetic acid or 0.01% HCl in water) providingthe trifluoro acetate or hydrochloride salts. The final productsexisting as salts may also be prepared in a separate salification stepby dissolution of the free base in ethanol or dichloromethane andtreatment of the solution with acid, e.g., 1N ethanolic HCl. Removal ofall volatiles under reduced pressure, affords the desired salt.

The table below sets out representative combinations of aryl halides andboronic acids that are reacted as described above in RepresentativeProcedure 5(a) or 5(b).

TABLE 7 Aryl Boronic Isolated Emax (%) ± E.g. Halide Acid MSA Form SEM210 1 1 494.4 Trifluoroacetate 30.8 ± 3.5 211 3 4 576.6 Trifluoroacetate84.2 ± 1.5 212 3 5 441.0 Hydrochloride 66.2 ± 2.6 213 3 3 491.5Hydrochloride 82.2 ± 4.8 214 3 2 507.1 Hydrochloride 67.1 ± 4.8 215 2 4631.7 Trifluoroacetate 82.4 ± 1.2 216 2 5 573.6 Trifluoroacetate 82.7 ±1.9 217 2 3 624.1 Trifluoroacetate 79.2 ± 1.6 218 2 2 639.7Trifluoroacetate 73.9 ± 2.0

Example 219

Potassium carbonate (14 mg) is added to 2 mL of dimethylsulfoxide. Themixture is stirred under nitrogen, and heated to 50° C. for 30 minutes.The mixture is cooled to room temperature, and the compound of Example115 (27 mg) dissolved in 2 mL of dimethylsulfoxide is added to themixture, followed by the addition of 0.5 mL of water dropwise. Themixture is allowed to stir for 10 to 15 minutes, then 0.1 mL of 30%hydrogen peroxide is added dropwise. After 20 minutes, 15 mL ofsaturated aqueous sodium sulfite solution and 5 ml water is added andthe mixture is extracted 3 times with 40 mL of ethyl acetate. Thecombined organic layers are dried with sodium sulfate, filtered andevaporated to give 28 mg of the free base of the title compound (100%).The free base is dissolved in methanol and 1 equivalent of succinic acid(6 mg) is added. The solvent is evaporated to obtain the title compound.FDMS m/e=557 (M⁺+1 of free base).

Example 220

The title compuond is prepared from the compound of Example 187 asdescribed for the preparation of Example 219. FDMS m/e=568.1 (M⁺+1)

Example 221

The crude residue containing the compound of Example 124 is dissolved intetrahydrofuran and 1.2 equivalents of lithium hydroxide is added. Thereaction mixture is stirred at ambient temperature overnight. Thereaction is concentrated, and purified on C18 bonded silica gel usingreverse phase liquid chromatography (acetonitrile/water with 0.1%trifluoroacetic acid). FDMS m/e 465.2.

Example 222

To a solution of the compound of Example 146 (1.02 mmol) in methanol isadded 10% Pd/C (100 mg/mmol of substrate) in methanol. The reactionmixture is purged with hydrogen and hydrogenation is carried out with ahydrogen balloon overnight. The reaction mixture is filtered and thefiltrate is evaporated to dryness to give the title compound. FDMSm/e=516.2 (M⁺+1).

Example 223

To a solution of the compound of Example 162 (200 mg, 0.43 mmol) inmethanol is added 2N NaOH (1.0 mL). The reaction mixture is heated torelux and is stirred at reflux for 18 hours. The reaction mixture iscooled to room temperature and evaporated to dryness. The residue istaken up in water (20 mL), acidified to pH 5.0 with 1.0 N HCl, andextracted with ethyl acetate (2×25 mL). The combined organic extractsare washed with brine, dried (Na₂SO₄) and filtered. The filtrate isevaporated to dryness to afford 50 mg of the title compound (25%). FDMSm/e=480.1 (M⁺+1).

Example 224

The title compound is prepared from the compound of Example 137 (200 mg,0.43 mmol) by a procedure substantially similar to that described forExample 223 to give 50 mg of the title compound (85%). FDMS m/e=495.2(M⁺+1).

Example 225

The compound of Example 224 (0.15 mmol) is dissolved in methanol (0.015mmol of solute/mL). 2 N NaOH is added, the reaction mixture is heated torelux and then stirred for 1.5 hours. The reaction is cooled to roomtemperature and the mixture is evaporated to about 2 mL and the residueis diluted to 20 mL with water. The resulting solution is passed througha C18 cartridge, washed eith water (50 mL) and eluted with methanol (25mL). The organic layer is evaporated to give a white solid (90%). FDMSm/e=495.2 (M⁺+1).

Example 226

To a solution of the compound of Example 224 (146 mg, 0.30 mmol) inmethanol (10 mL) is added NH₄Cl (15.8 mg, 0.30 mmole). The resultingsolution is evaporated to dryness. The residue is taken up in ethylacetate and evaporated to dryness to give 155 mg of the title compound(100%). FDMS m/e=495.1 (M⁺+1).

Example 227

To a solution of the compound of Example 147 in methanol (5 mL) is added1N NaOH (1.0 mL). The resulting solution is refluxed for 1 hour. Thereaction mixture is cooled to room temperature and evaporated todryness. The residue is taken up in water (10.0 mL), passed through aC18 cartridge, eluted with methanol (20 mL) and evaporated to dryness togive 45 mg of the title compound (50%). FDMS m/e 491.3 (M⁺+1).

Example 228

The title compound is prepared from the compound of Example 145 by aprocedure substantially similar to that described for the preparation ofExample 227. FDMS m/e=493.1 (M⁺+1).

Example 229

To a solution of the compound of Example 137 (250 mg, 0.52 mmol) intoluene (50 mL) is added dimethyltin oxide (43 mg, 0.26 mmol) andazidotrimethylsilane (600 mg, 5.2 mmol). The reaction mixture is heatedto relux overnight. The reaction mixture is cooled to room temperature,evaporated to dryness. The resulting residue is chromatographed with 20%methanol (2N ammonia) in dichloromethane to give 150 mg of the free baseof the title compound (56%). Succinic acid (34.1 mg, 0.289 mmol) inmethanol (1.0 mL) is added and the resulting mixture is allowed to stirbefore evaporating to dryness to give 18 mg of the title compound(100%). FDMS m/e=519.3 (M⁺+1).

Example 230

The free base of the title compound is prepared from the compound ofExample 143 (76 mg, 0.16 mmol) and azidotrimethylsilane (190 mg, 1.62mmol) by a procedure substantially analogous to that described inExample 229 to give the title compound. FDMS m/e=515.2 (M⁺+1).

Example 231

To a solution of the compound of Example 137 (87 mg, 0.18 mmol) inethanol (10.0 mL), is added cysteamine (25 mg, 0.22 mmol). The resultingmixture is reluxed overnight. The reaction mixture is cooled to roomtemperature and evaporated to dryness. The resulting residue ischromatographed (5% methanol (2N ammonia) in dichloromathane) to give 42mg of the free base of the title compound (44%). The succinate salt isprepared as described in Example 229 to give the title compound. FDMSm/e=536.0 (M⁺+1).

Example 232

The title compound is prepared from the compound of Example 144 andazidotrimethylsilane by a procedure substantially analogous to thatdescribed in Example 229 to give the title compound. FDMS m/e=517.2(M⁺+1).

Example 233

A solution of the compound of Example 23 (0.185 mmol) in 1.5 ml oft-butanol is treated with NaOH (100 mg). Ethanol (1.5 ml) is added toaid solubility, and the resulting mixture is heated at 80° C. for 6hours. The reaction mixture is concentrated in vacuo and purified byreverse phase HPLC (YMC ODSA C18 5 micrometer column, gradient of 5–95%CH₃CN in H₂O with 0.01% HCl, 20 ml/minute, over 12 minutes) to give 28.2mg of the title compound (30%).

Examples 234–237

The title compounds are separately prepared from the compound ofExamples 24, 151, 168 and 169, respectively, in a manner similar to thatdescribed in Example 233.

Example 238

A solution of crude free base of the product from Example 69 (195 mg,0.408 mmol) in 1.2 ml of 3:1:1 tetrahydrofuran:methanol:H₂O is treatedwith LiOH (30 mg, 1.25 mmol). The resulting mixture is heated for 2 daysat 70° C. then concentrated in vacuo. Purification of the crude productby reverse phase HPLC (YMC ODSA C18 5 micrometer column, gradient of5–95% CH₃CN in H₂O with 0.01% HCl, 20 ml/minute, over 12 minutes)affords 88.2 mg of the title compound (43%).

Examples 239–241

The title compounds are separately prepared by hydrolysis of crude freebase of the product from Examples 70, 75 and 76, respectively, in amethod similar to that detailed in Example 238.

Example 242

A solution of the free base of the compound of Example 153 (87.6 mg,0.189 mmol) in 1.2 ml of 3:1:1 tetrahydrofuran:methanol:H₂O is treatedwith LiOH (7 mg, 0.282 mmol). The resulting mixture is stirred atambient temperature for 11 days. Additional LiOH (7 mg, 0.282 mmol) isadded, and the mixture is heated overnight at 70° C. then concentratedin vacuo. Purification of the crude product by reverse phase HPLC (YMCODSA C18 5 micrometer column, gradient of 5–95% CH₃CN in H₂O with 0.01%HCl, 20 ml/minute, over 12 minutes) affords 31 mg of the title compound(34%).

Example 243

The title compound is prepared in 54% yield by hydrolysis of the freebase of the compound of Example 154 with LiOH in a manner similar tothat described in Example 242.

Example 244

The compound of Example 116 (97 mg) is dissolved in 6 mL of methanol.Sodium hydroxide (2N, 3 mL) is added and the mixture is refluxed for 16hours. Water (10 ml) is added and the pH of the mixture is adjusted to 3using 1N hydrochloric acid. The aqueous mixture is extracted with ethylacetate (3×50 mL). The combined organic extracts are dried withanhydrous sodium sulfate, filtered, and the solvent is evaporated. Theproduct is purified using HPLC (5–95% solvent B in 3.8 minutes on YMCODS-A (0.46×50 mm), solvent A=0.1% hydrochloric acid/water, solventB=0.1% hydrochloric acid/acetonitrile) to give 15.9 mg of the titlecompound. FDMS m/e=543 (M⁺+1 of free base).

Example 245

The crude title compound is prepared from he compound of Example 116 (97mg) via the procedure described in Example 219. The crude product ispurified using HPLC (5–95% solvent B in 3.8 minutes on YMC ODS-A(0.46×50 mm), solvent A=0.1% hydrochloric acid/water, solvent B=0.1%hydrochloric acid/acetonitrile) to give 60.8 mg of the title compound.FDMS m/e=542 (M⁺+1 of free base).

Example 246

To a solution of the compound of Example 178 (103 mg, 0.186 mmol) inmethanol (5 mL) is added sodium hydroxide (0.93 mL, 2M, 1.86 mmol). Themixture is refluxed for 4 hours then diluted with HCl and extractedthree times with ethyl acetate. The combined extracts are dried oversodium sulfate, filtered and evaporated. The residue is chromatographedby reverse phase HPLC (acetonitrile/0.01% HCl in water) to give thetitle compound (41%). FDMS m/e=541 (M⁺+1 of free base).

Example 247

The compound of Example 182 is converted to the title compound via theprocedure described for the preparation of the compound of Example 246(57%). FDMS m/e=526 (M⁺+1 of free base).

Example 248

The compound of Example 180 is converted to the title compound via theprocedure described for the preparation of the compound of Example 246(88%). FDMS m/e=541 (M⁺+1 of free base).

Example 249

The compound of Example 184 is converted to the title compound via theprocedure described for the preparation of the compound of Example 246(32%). FDMS m/e=526 (M⁺+1 of free base).

Example 250

The compound of Example 181 is converted to the title compound via theprocedure described for the preparation of the compound of Example 246except that chromatography on the crude free base is not performed.Instead, the crude free base is dissolved in a small amount of ethylacetate and treated with 1 equivalent of succinic acid in methanol. Theresulting slurry is dissolved in the minimum amount of methanol thenconcentrated in vacuo to give the title compound (78%). FDMS m/e=547(M⁺+1 of free base).

Examples 251 and 252

The title compounds are separately prepared from the compound ofExamples 187 and 190, respectively, as described in Example 229. FDMSm/e=593.1 (M⁺+1) and FDMS m/e=515.2 (M⁺+1).

The title compounds are separately prepared from the compound of Example188, the compound of Example 189 and the compound of Example 252,respectively, as described for the preparation of Example 222. FDMSm/e=527.2 (M⁺+1), 604.2 (M⁺+1) and FDMS m/e=517.24 (M⁺+1).

Example 256

The compound of Example 1 (8.87 g, 18.8 g, 1.00 equivalent) is treatedall at once with concentrated HCl (1.57 mL, 0.95 equivalents) in ethylacetate (221 mL, 25° C.). The ethyl acetate is evaporated under vacuumand the solid stirred with 250 mL of diethyl ether (3 hours) after whichthe mixture is filtered and the resulting solid dried under a stream ofnitrogen to afford 8.98 g of the title compound (93%). MS: 459.2.

Example 257

A solution of the crude free base of Example 99 (285 mg, 0.64 mmol) in7.5 ml of dimethylsulfoxide is treated with powdered K₂CO₃ (177 mg, 1.28mmol). The resulting mixture is cooled to 0° C., and 73 μl of 30% H₂O₂is added dropwise. After stirring overnight, 1 ml of 20% KOH and anadditional 200 μl of 30% H₂O₂ is added to the reaction mixture. Afterstirring overnight, 20 ml of H₂O is added, and the resulting mixture iscooled in an ice-H₂O bath for 1 hour, then extracted with CHCl₃. Theorganic layer is washed with brine, dried over Na₂SO₄ and concentratedin vacuo. The residue is purified by reverse phase HPLC (YMC ODSA C18 5μm column, gradient of 5–95% CH₃CN in H₂O with 0.01% HCl, 20 ml/minute,over 12 minutes) to give 25 mg of the title compound (8%). MS 464.2.

Examples 258 and 259

To solution of the compound of Example 216 in dry ethanol is added 10%HCl in ethanol and the mixture is stirred at room temperature. Thesolvent is evaporated, the residue re-dissolved in ethanol and loaded ona SCX column. After washing with ethanol, the products are eluted with10% NH₃ in ethanol, evaporated, separated and purified via preparativeHPLC (C18 bonded silica gel reverse phase liquid chromatography(acetonitrile/water with 0.1% trifluoroacetic acid) to give the titlecompounds.

Examples 260 and 261

The title compounds are prepared as described for Examples 258 and 259from the compound of Example 218.

The table below sets out Emax data collected for the compounds ofExamples 219–261.

TABLE 8 Emax (%) ± E.g. SEM 219 85.9 ± 9.4 220 81.2 ± 0.6 221 74.6 ± 3.6222 81.2 ± 0.9 223 56.1 ± 2.8 224 94.3 ± 4.6 225 78.1 ± 4.6 226 70.3 ±5.7 227 87.5 ± 7.5 228 79.5 ± 0.6 229 83.0 ± 2.5 230 81.3 ± 2.4 231 85.0± 4.9 232 79.5 ± 1.7 233 52.4 ± 6.0 234 66.4 ± 6.4 235 76.7 ± 4.4 23688.4 ± 3.9 237 73.9 ± 2.9 238 <10 239 69.6 ± 3.5 240 78.7 ± 2.4 241 70.1± 0.6 242 59.6 ± 2.8 243 48.4 ± 2.5 244 77.0 ± 2.1 245 63.3 ± 3.0 24679.2 ± 3.4 247 54.6 ± 2.4 248 84.1 ± 1.8 249 68.8 ± 7.8 250 92.5 ± 5.1251 86.3 ± 3.4 252 82.3 ± 4.0 253 81.6 ± 4.0 254 80.9 ± 4.9 255 83.9 ±3.2 256 71.4 ± 2.7 257 81.8 ± 8.5 258 76.8 ± 2.1 259 84.2 ± 2.9 260 77.0± 3.4 261 75.8 ± 3.8Demonstration of Function

The genes encoding the human β₁-adrenergic receptor (Frielle et al.,Proc. Natl. Acad. Sci., 84:7920–7924, 1987), the human β₂-adrenergicreceptor (Kobika et al., Proc. Natl. Acad. Sci., 84:46–50, 1987, Emorineet al., Proc. Natl. Acad. Sci., 84:6995–6999, 1987) and the human β₃adrenergic receptor (Granneman et al., Molecular Pharmacology,44(2):264–70, 1993) are individually subcloned into a phd expressionvector (Grinnell et al., Bio/Technology, 5:1189–1192, 1987) andtransfected into the DXB-11 Chinese hamster ovary (CHO) cell line bycalcium phosphate precipitation methodology. The stably transfectedcells are grown to 95% confluency in 95% Dulbecco's modified EaglesMedium (DMEM), 5% fetal bovine serum and 0.01% proline. Media is removedand the cells are washed with phosphate buffered (pH 7.4) saline(without magnesium and calcium). Cells are then lifted using an enzymefree cell dissociation solution (Specialty Media, Lavallette, N.J.) andpelleted by centrifugation.

Cells from each of the above cell lines are resuspended and added(20,000/well) to a 96-well plate. Cells are incubated at 37° C. withrepresentative compounds of the invention for 20 minutes in buffer(Hank's balanced salt solution, 10 mM HEPES, 0.1% BSA, 1 mM L-ascorbicacid, 0.2% dimethyl sulfoxide, 1 mM 3-isobutyl-1-methylxanthine, pH7.4). After halting the incubation with quench buffer (50 mM Na Acetate,0.25% Triton X-100, pH 5.8), the c-AMP level is quantified byscintillation proximity assay (SPA) using a modification of thecommercially available c-AMP kit (Amersham, Arlington Heights, Ill.)with rabbit anti-cAMP antibody (ICN Biomedicals, Aurora, Ohio) for thekit.

Sigmoidal dose response curves, from the whole cell receptor coupledc-AMP assay are fit to a four parameter logistic equation using nonlinear regression: y=(a−d)/(1+(Dose/c)^(b))+d where a and d areresponses at zero and maximal dose, b is the slope factor and c is theEC₅₀ as previously described (DeLean et al., Am. J. Physiol., 235,E97-E102, 1978). EC₅₀ is assessed as the concentration producing 50% ofthe maximum response to each agonist.

Isoproterenol is accepted in the art as a non-selective β₃ agonist andis widely used as a comparator in evaluating the activity of compounds.See Trends in Pharm. Sci., 15:3, 1994. The % intrinsic activity (Emax)of representative compounds of the invention is assessed relative toisoproterenol by the compound's maximal response divided by theisoproterenol maximal response times 100.

In vitro Rat Atrial Tachycardia

Male rats (250–350 g) (Harlan Sprague Dawley, Indianapolis, Ind., USA)are killed by cervical dislocation. Hearts are removed and the left andright atria are dissected and mounted with thread in tissue bathscontaining 10 mls of modified Krebs' solution. Initial resting tensionis 1.5–2.0 g at the outset of the experiment (Naunyn-Schmied Arch.Pharmacol., 320:145, 1982). Tissues are allowed to equilibrateapproximately 30 minutes with vigorous oxygenation before exposure to acompound of the invention. To evaluate the ability of test compounds toincrease heart rate, representative compounds of the present inventionare added cumulatively once the atrial rate reached a steady state fromthe previous addition. Compound addition is continued until no furtherincrease in atrial rate occurred or until a concentration of 10⁻⁴M isreached. The increase in beats per minute (bpm) is measured for eachconcentration of test compound by means of a BioPac System (Br. J. ofPharmacol., 126:1018–1024, 1999).

Utilities

As agonists of the β₃ receptor, the salts of the present invention areuseful in treating conditions in human and non-human animals in whichthe β₃ receptor has been demonstrated to play a role.

The diseases, disorders or conditions for which compounds of the presentinvention are useful in treating include, but are not limited to, (1)diabetes mellitus, (2) hyperglycemia, (3) obesity, (4) hyperlipidemia,(5) hypertriglyceridemia, (6) hypercholesterolemia, (7) atherosclerosisof coronary, cerebrovascular and peripheral arteries, (8) hypertension,(9) disorders of the gall bladder including acute and chroniccholecystitis, (10) depression, (11) elevated intra-ocular pressure andglaucoma, (12) non-specific diarrhea dumping syndrome, (13) hepaticsteatosis [fatty degeneration of the liver], and obesity dependentdiseases/disorders such as: (14) gastrointestinal disorders includingpeptid ulcer, esophagitis, gastritis and duodenitis, (including thatinduced by H. pylori), intestinal ulcerations (including inflammatorybowel disease, ulcerative colitis, Crohn's disease and proctitis) andgastrointestinal ulcerations, (15) irritable bowel syndrome and otherdisorders needing decreased gut motility, (16) diabetic retinopathy,(17) neuropathic bladder dysfunction, (18) osteoarthritis, (19)restrictive lung disease, (20) obstructive sleep apnea, (21) congestiveheart failure, (22) venous stasis and skin disorders related to venousstasis, (23) decreased libido (in both males and females), and (24)acute and chronic cystitis. The term “obesity dependent” means that thesymptoms of said diseases will be ameliorated via the present salt'seffect on the patient's weight.

Human patients in need of obesity treatment are typically those with abody mass index (BMI)>27 or those with a BMI≧25 when co-morbidities,e.g., hypertension, sleep apnea and/or osteoarthritis, are present. Apatient population at particular need of treatment are those with aBMI>30 or >27 with co-morbities.

Human patients in need of hypertension treatment are frequentlyoverweight individuals, i.e., those with a BMI≧95, but may also be ofnormal body weight (i.e., BMI<25).

Human patients in need of type 2 diabetes treatment are typicallyindividuals with a BMI<25, i.e., individuals that are not overweight.

Formulation

The compound of formula I is preferably formulated in a unit dosage formprior to administration. Therefore, yet another embodiment of thepresent invention is a pharmaceutical formulation comprising a compoundof formula I and a pharmaceutical carrier.

The present pharmaceutical formulations are prepared by known proceduresusing well-known and readily available ingredients. In making theformulations of the present invention, the active ingredient (formula Icompound) will usually be mixed with a carrier, or diluted by a carrier,or enclosed within a carrier which may be in the form of a capsule,sachet, paper or other container. When the carrier serves as a diluent,it may be a solid, semisolid or liquid material which acts as a vehicle,excipient or medium for the active ingredient. Thus, the compositionscan be in the form of tablets, pills, powders, lozenges, sachets,cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosol (asa solid or in a liquid medium), soft and hard gelatin capsules,suppositories, sterile injectable solutions and sterile packagedpowders.

Some examples of suitable carriers, excipients, and diluents includelactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia,calcium phosphate, alginates, tragacanth, gelatin, calcium silicate,microcrystalline cellulose, polyvinylpyrrolidone, cellulose, watersyrup, methyl cellulose, methyl and propylhydroxybenzoates, talc,magnesium stearate and mineral oil. The formulations can additionallyinclude lubricating agents, wetting agents, emulsifying and suspendingagents, preserving agents, sweetening agents or flavoring agents. Thecompositions of the invention may be formulated so as to provide quick,sustained or delayed release of the active ingredient afteradministration to the patient.

FORMULATION 1 Tablets Ingredient Quantity (mg/tablet) Active Ingredient5–500 Cellulose, microcrystalline 200–650  Silicon dioxide, fumed10–650  Stearate acid 5–15 The components are blended and compressed to form tablets.

FORMULATION 2 Suspensions Ingredient Quantity (mg/5 ml) ActiveIngredient 5–500 mg Sodium carboxymethyl cellulose 50 mg Syrup 1.25 mgBenzoic acid solution 0.10 ml Flavor q.v. Color q.v. Purified water to 5mlThe medicament is passed through a No. 45 mesh U.S. sieve and mixed withthe sodium carboxymethyl cellulose and syrup to form a smooth paste. Thebenzoic acid solution, flavor, and color are diluted with some of thewater and added, with stirring. Sufficient water is then added toproduce the required volume.

FORMULATION 3 Intravenous Solution Ingredient Quantity Active Ingredient25 mg Isotonic saline 1,000 mlThe solution of the above ingredients is intravenously administered to apatient at a rate of about 1 ml per minute.Dose

The specific dose administered is determined by the particularcircumstances surrounding each situation. These circumstances include,the route of administration, the prior medical history of the recipient,the pathological condition or symptom being treated, the severity of thecondition/symptom being treated, and the age and sex of the recipient.However, it will be understood that the therapeutic dosage administeredwill be determined by the physician in the light of the relevantcircumstances.

Generally, an effective minimum daily dose of a compound of formula I isabout 5, 10, 15, or 20 mg. Typically, an effective maximum dose is about500, 100, 60, 50, or 40 mg. Most typically, the dose ranges between 15mg and 60 mg. The exact dose may be determined, in accordance with thestandard practice in the medical arts of “dose titrating” the recipient;that is, initially administering a low dose of the compound, andgradually increasing the does until the desired therapeutic effect isobserved.

Route of Administration

The compounds can be administered by a variety of routes including theoral, rectal, transdermal, subcutaneous, topical, intravenous,intramuscular or intranasal routes.

Combination Therapy

The compound of formula I may be used in combination with other drugsthat are used in the treatment of the diseases or conditions for whichthe present salts are useful, e.g., treatment of obesity and/or type 2diabetes. Such other drug(s) may be administered, by a route and in anamount commonly used therefore, contemporaneously or sequentially with acompound of the present invention. When a compound of the presentinvention is used contemporaneously with one or more other drugs, apharmaceutical unit dosage form containing such other drugs in additionto the present salt is preferred. Accordingly, the pharmaceuticalcompositions of the present invention include those that also containone or more other active ingredients, in addition to a compound of thepresent invention.

1. A compound of the formula:

wherein: m is 0 or 1; Het is selected from furan; isoxazole; oxazole;tetrazole and thiophene; wherein said Het moieties are optionallysubstituted once with methyl, cyano, SO₂NH₂ or COCH₃; R⁷ is H, CO₂H;CH₂CH₂R¹¹; thienyl substituted once with CO₂H; phenyl substituted oncewith CO₂H; OCH₂CONHSO₂(C₁–C₄ alkyl); OCH₂CH₂NHSO₂(C₁–C₄ alkyl); OCH₂CN;OCH₂CO₂R¹⁷; OCH₂CONR¹⁸R¹⁸; O(pyridine) wherein said pyridine moieity issubstituted once with cyano or CO₂H; OCH₂(tetrazole);OCH₂(4,5-dihydrothiazole); or NHSO₂R¹⁰; R¹⁰ is C₁–C₄ alkyl or phenyl;R¹¹ is CO₂R¹⁶; CONR¹⁶R¹⁶; 1,2,3,4-tetrazole; or phenyl substituted oncewith SO₂NR²²R²²; R¹⁶, R¹⁷, R¹⁸ and R²² are independently H or C₁–C₄alkyl at each occurrence; and R¹⁹ and R²⁰ are independently H or methylat each occurrence; or a pharmaceutical salt thereof.
 2. The compound ofclaim 1 of the formula:

wherein: Het is thien-2-yl optionally substituted once with cyano,SO₂NH₂ or COCH₃; R⁷ is H; CO₂H; CH₂CH₂R¹¹; OCH₂CN; OCH₂CO₂H;OCH₂(tetrazole); thienyl substituted once with CO₂H or phenylsubstituted once with CO₂H; or NHSO₂R¹⁰; R¹⁰ is C₁–C₄ alkyl or phenyl;and R₁₁ is 1,2,3,4-tetrazole; or a pharmaceutical salt thereof.
 3. Thecompound of claim 2 which is:

or a pharmaceutical salt thereof.
 4. The compound of claim 3 which isthe hydrochloride salt.
 5. A compound which is:

or a pharmaceutical salt thereof.
 6. A method of treating Type 2Diabetes comprising administering to a patient in need thereof acompound of claim
 1. 7. A method of treating obesity comprisingadministering to a patient in need thereof a compound of claim 1.